# projects

application_id: 9235143
project_number: 5P01CA163223-05
project_title: Determining Molecular Mechanisms of NSCLC and Response to beta-glucan
administering_ic: NCI
award_notice_date: 2017-02-21
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
project_end_date: 2020-02-29
study_section: ZCA1-RPRB-0
subproject_number: 7603
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-03-01
project_abstract:
The gold standard for understanding the connection between tumor metabolism tumor progression and ultimately therapeutic efficacy is the human subject but more detailed information is needed from appropriate better controlled models. We have begun a Stable Isotope Resolved Metabolomics (SIRM) study of non-small cell lung cancer (NSCLC) from patients who underwent surgical resection. In our pilot study we capitalized on the inherent power of the matched pairs of malignant and benign lung tissue and the use of "C-labeled glucose administered iv prior to surgery to map in situ intracellular metabolic pathways for the first time. This led to the discovery that mitochondrial pyruvate carboxylase (PCB) is activated to replenish Krebs cycle intermediates required for biosynthesis (i.e. anaplerosis) in tumors. This was further corroborated by increased mRNA and protein expression of PCB in the tumors compared with the paired benign lung tissue as well as growth inhibition of NSCLC cells by PCB knockdown. Critical to the interpretation of these studies was the additional detailed information that we obtained on cell culture and mouse models which provided metabolic signatures to look for in the tumor tissue.). Our preliminary findings also indicate that there are many more metabolic distinctions in lung tumors; the underlying pathways and regulation have yet to be defined. We now seek to extend the approach to a larger cohort of NSCLC and added a new ex vivo "Warburg" tissue slice approach to better define in large-scale the metabolic reprogrammings in NSCLC with prevailing driver gene defects. These direct human studies will be conducted in parallel with model cell (Project 1) and animal studies (Project 2) to facilitate interpretation. We will also apply this integrated approach to explore the metabolic mechanism underlying the tumor-regressive effect of a pre-operative treatment with beta-glucans. We hypothesize that this effect may be in part mediated by beta-glucan's activation of glucose and Gin metabolism in resident macrophages a key immune modulator in the tumor microenvironment based on our most recent data and the literature (cf. Project 2). We will further explore the linkage of lung tumor tissue to blood plasma metabolism via the lipidic microvesicles (MV) known to be released by lung cancer cells with metastasis-promoting capacity. We have new evidence that the lipid profile of plasma MV is distinct among early stages of lung and breast cancer patients and healthy subjects. We will test if beta-glucan treatment can alter MV metabolic signatures for future application as clinical indicators. These goals will be achieved via the three specific aims.

project_terms:
Adenocarcinoma Cell;Age;Anabolism;Animals;Benign;Biochemical;Biochemistry;Breast Cancer Patient;Cancer Patient;Carcinoma in Situ;Cell Culture Techniques;Cell model;Cells;Cessation of life;Characteristics;Citric Acid Cycle;Clinical;Coupled;Data;Defect;Early Diagnosis;Excision;Future;Gene Expression Profile;Genes;Glucose;Glutamine;Goals;Gold;Growth;Human;Immune;Immune response;In Situ;Infusion procedures;Knowledge;Label;Learning;Link;Lipids;Literature;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Molecular;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;North America;Oncogenes;Oncogenic;Operative Surgical Procedures;Outcome;Pathologic;Pathway interactions;Patients;Pilot Projects;Plasma;Pyruvate Carboxylase;Recruitment Activity;Regulation;Resected;Sample Size;Sampling;Slice;Squamous cell carcinoma;Structure of parenchyma of lung;System;Testing;Therapeutic;Time;Tissues;Tracer;Treatment Efficacy;Tumor Subtype;Tumor Tissue;Tumor stage;Tumor-Derived;base;beta-Glucans;cancer cell;cancer subtypes;cohort;design;diagnostic biomarker;human subject;improved;knock-down;mRNA Expression;macrophage;metabolomics;microvesicles;mouse model;novel diagnostics;novel strategies;outcome forecast;protein expression;response;stable isotope;tumor;tumor metabolism;tumor microenvironment;tumor progression

public_health_relevance:
RELEVANCE (See instructions): Deaths from lung cancer are the highest among all cancers in North America and cure rates remain low. We seek to gain a deeper understanding of lung cancer biochemistry using a novel approach we developed. Improved knowledge will have direct impact on early diagnosis and prognosis. The biochemical differences between lung cancer subtypes can be related to appropriate treatments.


application_id: 9235142
project_number: 5P01CA163223-05
project_title: Determining Tumor Metabolism and Biochemical Mechanism of beta-glucan Action in
administering_ic: NCI
award_notice_date: 2017-02-21
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
project_end_date: 2020-02-29
study_section: ZCA1-RPRB-0
subproject_number: 7602
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-03-01
project_abstract:
Deaths from lung cancer are the highest of all cancers in the US. The complexity of lung cancer (LC) development suggests that a combination of approaches is needed to understand the mechanism of LC biology and tumor cell interactions with other cells such as immune cells within the tumor microenvironment. The concept of "cancer immunoediting" recognizes the complex and dynamic interactions between the tumor and host during tumor development progression and metastasis. Although how the immune system plays a role in development and progression of human non-small cell lung carcinoma (NSCLC) is still elusive innate macrophages are abundant in the NSCLC tumors. These macrophages are of immune suppressive M2 phenotype promote tumor angiogenesis and metastasis and limit efficacy of chemotherapy for NSCLC. beta-Glucans polysaccharides derived from various sources can stimulate both innate and adaptive immune responses. Our preliminary data further demonstrate that beta-glucan treatment in vitro converts immune suppressive M2 macrophages into tumoricidal M1 phenotype and significantly decreases tumor-associated macrophage (TAM)-mediated immune suppression on CD4 and CDS T cells. Using the stable isotope resolved metabolomics (SIRM) approach we show that glutamine (Gin) uptake and subsequent metabolism to glucose glutathiones and lactate are enhanced when immune suppressive M2 macrophages are converted into an Ml phenotype. The central hvpothesis of this proposal is that differential human NSCLC subtypes may have distinct metabolic profiles and p-glucan treatment modulates TAM activity and metabolism leading to the alterations of metabolic networks in NSCLC. We will use stable isotopic (13C 15N) nutrient tracers in combination with the SIRM approach and metabolomics-edited transcriptomic analysis (META) to define key metabolic components of human NSCLC in vivo and investigate how beta-glucan treatment influences TAM phenotype function metabolism and subsequently tumor microenvironmental metabolic events. Three Specific Aims are proposed to determine the: 1 specific metabolic patterns of human NSCLC cells in xenografted tumors in severe combined immunodeficient (SCID) mice; 2) biochemical mechanisms of beta-glucan action in murine lung carcinoma models; 3) biochemical and phenotypic characteristics of human primary tumors implanted in N0D/SCID/IL-2gcNULL mice in response to beta-glucan administration. These investigations will advance our understanding of the biochemical underpinnings of tumor microenvironment nutrient utilization by NSCLC and how these processes are related to tumor immune evasion and immunomodulation.

project_terms:
Affect;Antigen Presentation;Arginine;Biochemical;Biochemical Pathway;Biochemistry;Cancer Biology;Cell Communication;Cell Line;Cells;Cessation of life;Clinical;Complex;Data;Development;Early Diagnosis;Event;Genes;Glucans;Glucose;Glutamine;Glutathione;Goals;Human;Human Characteristics;Immune;Immune Evasion;Immune system;Immunomodulators;Immunophenotyping;Implant;In Situ;In Vitro;In Vivo NMR Spectroscopy;Instruction;Investigation;Knowledge;Label;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Measurement;Mediating;Mediator of activation protein;Metabolic;Metabolism;Modeling;Mus;Natural immunosuppression;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;North America;Nutrient;Outcome;Particulate;Pathway Analysis;Pathway interactions;Patients;Pattern;Phenotype;Play;Polysaccharides;Primary Neoplasm;Process;Protein Analysis;Role;SCID Mice;Slice;Source;System;T-Lymphocyte;Tissues;Tracer;Tumor Angiogenesis;Yeasts;adaptive immune response;angiogenesis;beta-Glucans;cancer cell;cancer subtypes;chemotherapy;immunoregulation;improved;in vivo;lung Carcinoma;macrophage;metabolic profile;metabolomics;neoplastic cell;novel strategies;outcome forecast;response;stable isotope;subcutaneous;transcriptomics;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumor xenograft;uptake


application_id: 9235138
project_number: 5P01CA163223-05
administering_ic: NCI
award_notice_date: 2017-02-21
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
project_end_date: 2020-02-29
study_section: ZCA1-RPRB-0
subproject_number: 7601
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-03-01
budget_end_date: 2018-02-28
project_title:
Microenvironmental Nutrient Availability and Immunomodulation in Lung Cancer Cells: A systems biochemical approach

project_abstract:
PROJECT SUMMARY (See instructions); We propose a systems biochemical study of lung cancer (LC) cell nutrient metabolism of importance to LC development survival and progression in the tumor microenvironment (TME). The primary approach is to utilize stable isotopic (13C and 15N) nutrient tracers in conjunction with stable isotope-resolved metabolomics (SIRM) and metabolomics-edited transcriptomic analysis (META) to discern key metabolic events in LC cells that govern their behavior and vulnerability in response to major TME factors such as hypoxia and nutrient deficiency. A central focus of this cell-based project is to understand the interaction of nutrient availability and hypoxia in modulating LC cell metabolism and how this may affect its ability to grow survive and progress. This focus is in part motivated by our recent finding from the gene array data of paired cancerous and benign lung tissues resected from human patients regarding the dysregulations of key enzymes (e.g. arginase glutaminase hyaluronan synthase 2) involved in metabolism of glutamine and glucose. It is also driven by our recent discovery of arginase suppression in lung tumor xenograft and activation of Gin metabolism in murine macrophages by a natural immune activator B-glucan. We will accomplish this with the following specific aims: SAI: SIRM profiling of lung cells for reconstructing biochemical pathways involved in utilization of glucose and glutamine. Biochemical pathways of these nutrients relevant to energy anabolism immunomodulatory sensors and cell migration-related extracellular matrix factors will be mapped in LC cells harboring major driver gene anomalies normal epithelial cells and relevant stromal cells for comparison. SA2: Probe interactions of nutrient availability in combination with hypoxia. We will focus on 2 key questions: 1) How does Gin alleviate glucose demand by LC cells?; 2) Is Gin metabolism crucial to hypoxic LC cells?. SAS: Examine Arg metabolism in human tumor-associated macrophages as a function of Gin and Arg availability. Gin and Arg utilization pathways of relevance to immunomodulation in tumor-associated human macrophages will be probed in response to immune activator (B-glucans) and M2 to Ml polarization. The knowledge gained from this project will be used to help interpret data obtained from Projects 2 and 3.

project_terms:
Affect;Alpha Cell;American;Anabolism;Apoptosis;Behavior;Benign;Biochemical;Biochemical Pathway;Biochemistry;Cancer cell line;Cancerous;Cell Line;Cells;Cessation of life;Citric Acid Cycle;Clinical;Colon Carcinoma;Data;Development;Early Diagnosis;Enzymes;Epidermal Growth Factor Receptor;Epithelial Cells;Event;Extracellular Matrix;Fibroblasts;Food Interactions;Gene Expression;Genes;Glucans;Gluconeogenesis;Glucose;Glutaminase;Glutamine;Glutathione Metabolism Pathway;Glycolysis;Goals;Growth;HAS2 gene;Hexosamines;Human;Hyaluronan;Hypoxia;Immune;Instruction;KRAS2 gene;Killings;Knowledge;Label;Link;Lung;Lung Neoplasms;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Maps;Mediating;Medicine;Metabolic;Metabolic Pathway;Metabolism;Methods;Modification;Mus;Nitric Oxide;Non-Small-Cell Lung Carcinoma;North America;Nutrient;PIK3CA gene;Pathway interactions;Patients;Pattern;Pentosephosphate Pathway;Polyamines;Proteins;Regulation;Research;Resected;Stable Isotope Labeling;Stromal Cells;Structure of parenchyma of lung;Surface;System;TP53 gene;Testing;Therapeutic;Tissues;Tracer;Tumor Tissue;Tumor-Derived;Yeasts;arginase;base;beta-Glucans;cancer cell;cancer subtypes;cell growth;cell motility;cell stroma;cytokine;immune function;immunoregulation;improved;in vivo;interest;lipid metabolism;macrophage;malignant breast neoplasm;metabolomics;mortality;novel;novel strategies;nucleotide metabolism;nutrient metabolism;outcome forecast;response;sensor;stable isotope;transcriptomics;tumor;tumor metabolism;tumor microenvironment;tumor xenograft;tumorigenesis;urea cycle


application_id: 9235136
project_number: 5P01CA163223-05
project_title: Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLC
administering_ic: NCI
award_notice_date: 2017-02-21
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
program_official: WILLIS, KRISTINE AMALEE
project_start_date: 2014-08-19
project_end_date: 2020-02-29
study_section: ZCA1-RPRB-0(O1)
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Deaths from lung cancer are the highest of all cancers in North America and elsewhere and because of the long incubation time are likely to remain so for the foreseeable future. Furthermore although the 5-year survival rate of stage I lung cancer is 60-70% later stage disease has a very poor prognosis. Accurate detection of asymptomatic early stage lung cancer in individuals at risk is currently unreliable. A better understanding of the basic biochemistry of lung cancers is a prerequisite to mechanism-based reliable early detection of the disease and to improved approaches to treatment. The very complexity of the transformed cells and the variable host-tumor interactions makes the problem refractory to any single approach. A systems biochemistry approach in which lung cancers are studied at the mechanistic level in the laboratory in mouse models and in human subjects offers the opportunity to address the complexity of cancer development and progression. The use of stable isotope resolved metabolomics provides the necessary direct biochemical information about lung cancer with minimal processing that is not otherwise available. This program will address the problem in a 3-pronged approach based on the following integrated projects: Project 1: Cellular Systems Biochemistry. Microenvironmental nutrient availability and immune modulation in lung cancer cells. Project 2; Preclinical Systems Biochemistry. Using SIRM in Human NSCLC xenograft mouse to determine biochemical mechanisms of immunomodulator -glucan.    
Project 3: Translational Systems Biochemistry. Molecular mechanisms of NSCLC and response to -glucan by SIRM. The three projects will use a common mechanistic approach to understanding cancer biochemistry namely stable isotope resolved metabolomics (SIRM) that we have been developing over the last eight years. The analytical requirements will be met in the SIRM Analytical Core which also supplies the necessary sample handling and bioinformatics support for the three projects. Core A provides overall administrative support.

project_terms:
Address;Analytical Biochemistry;Animal Model;Animals;Arginine;Benign;Biochemical;Biochemical Pathway;Biochemistry;Bioinformatics;Biometry;Cancer Biology;Cell Culture Techniques;Cell model;Cells;Cessation of life;Clinical Trials;Collaborations;Congresses;Data;Death Rate;Detection;Development;Disease;Early Diagnosis;Epithelial Cells;Fibroblasts;Food Interactions;Future;Generations;Genes;Glucans;Glucose;Glutamine;Goals;Human;Hypoxia;Immune;Immune system;Immunomodulators;Implant;In Situ;Individual;Informatics;Investigation;Knowledge;Label;Laboratories;Link;Lung;Lung Neoplasms;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Mediating;Metabolic;Metabolic Pathway;Metabolism;Modeling;Molecular;Mus;Mutation Analysis;Natural Products;Nature;Non-Small-Cell Lung Carcinoma;North America;Nutrient;Pathway Analysis;Patients;Pattern;Physicians;Plasma;Process;Property;Proteomics;Refractory;Resected;Resolution;Risk;Role;Sampling;Scientist;Slice;Structure of parenchyma of lung;Study Subject;Survival Rate;System;Technology;Testing;Thinness;Time;Tissues;Tumor-Derived;Xenograft procedure;arginase;base;beta-Glucans;cancer cell;cancer subtypes;cell transformation;cohort;exosome;experimental study;host neoplasm interaction;human subject;human tissue;immune activation;immunoregulation;improved;insight;interest;lung xenograft;macrophage;metabolic phenotype;metabolomics;mouse model;neoplastic cell;novel strategies;oncology;outcome forecast;pre-clinical;programs;response;stable isotope;subcutaneous;tool;transcriptomics;treatment strategy;tumor;tumor immunology;tumor metabolism;tumor microenvironment;tumor progression

public_health_relevance:
RELEVANCE: Deaths from lung cancer are the highest among all cancers in North America and cure rates remain low. We seek to gain a deeper understanding of lung cancer biochemistry using a novel approach we developed. Improved knowledge will have direct impact on early diagnosis and prognosis. The biochemical differences between lung cancer subtypes can be related to appropriate treatments.


application_id: 9234945
project_number: 1R03HS024488-01A1
administering_ic: AHRQ
award_notice_date: 2016-09-13
opportunity_number: PA-15-147
application_type: 1
activity_code: R03
ic: HS
serial_number: 024488
suffix: A1
program_official: WYATT, DERRICK
project_start_date: 2016-09-30
project_end_date: 2018-02-28
study_section: Healthcare Information Technology Research[HITR]
contact_pi_person_id: 9727845
contact_pi: SALEEM, JASON JAMIL
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Ambulatory Clinic Exam Room Design with Respect to Computing Devices to Enhance Patient Centeredness

project_abstract:
PROJECT SUMMARYAlthough much research has been conducted on the impact of the electronic health record (EHR) and healthinformation technology (HIT) on provider-patient interaction challenges persist on how to effectivelyintegrate these tools into healthcare environments while maintaining patient-centered care. We propose amulti-method study to investigate and improve the exam room and computing layout to improve clinicalworkflow and patient-centeredness which may ultimately enhance patient safety in the Veterans HealthAdministration (VHA). The Specific Aims are:Aim 1: Prototype and evaluate a redesigned exam room layout with respect to the exam room computingand compare the redesigned layout to a current typical exam room layout in the Veterans HealthAdministration (VHA).Aim 2: Refine the redesigned exam room layout implement it in a live clinic setting and compare it tocurrently designed exam rooms in a Veterans Affairs (VA) Medical Center.To achieve Aim 1 we propose a human in the loop simulation study in the Center for Ergonomicslaboratory space at the University of Louisville to pilot test a redesigned exam room layout with respect tothe exam room computing. In the proposed simulation study improved system design can be demonstratedthrough measures of efficiency accuracy workload patient-centeredness time spent screen sharingworkflow integration and situation awareness. Each of these measures will be used to compare a currenttypical exam room layout with the redesigned layout in a simulated setting.To achieve Aim 2 we propose a pilot implementation based upon actual patient visits in a live clinic. Wewill collect measures of patient-centeredness screen sharing workflow integration and situation awarenessin both the redesigned exam room and current exam rooms to understand the impact of the redesignedexam room layout. The intention of the live clinic study is to gather additional field data to support thefindings from the laboratory simulation study and ultimately to have confidence our intervention for alarger study that would support broad dissemination of the redesigned exam room layout VHA-wide.Through these aims we will refine and finalize a new exam room design for the VHA grounded in asociotechnical systems perspective. We expect the knowledge generated by this study will be generalizableacross different healthcare organizations for enhancing patient-centeredness with regard to exam roomcomputing.

public_health_relevance:
NARRATIVEAlthough much research has been conducted on the impact of the electronic health record (EHR) and healthinformation technology (HIT) on provider-patient interaction challenges persist on how to effectivelyintegrate these tools into healthcare environments while maintaining patient-centered care. We propose amulti-method study to investigate and improve the exam room layout with respect to the exam roomcomputing to improve clinical workflow and patient-centeredness which may ultimately enhance patientsafety in the Veterans Health Administration (VHA).


application_id: 9234823
project_number: 1R01NR016824-01
project_title: Rural Intervention for Caregivers' Heart Health (RICHH)
administering_ic: NINR
award_notice_date: 2016-09-23
opportunity_number: RFA-NR-16-003
application_type: 1
activity_code: R01
ic: NR
serial_number: 016824
program_official: HUSS, KAREN
project_start_date: 2016-09-26
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZNR1 REV-M (25)]
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
other_pis: CHUNG, MISOOK LEE
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adherence;Adult;American;Americas;Behavior;Blood Pressure;Body mass index;Cardiac health;Cardiovascular Diseases;Caregivers;Caring;Cessation of life;Chronic Disease;Chronically Ill;Communication;Computer software;Control Groups;Data;Development;Devices;Diagnostic;Diet;Distress;Economically Deprived Population;Enrollment;Environment;Epidemic;Family;Family Caregiver;Family member;Female;Gender;Goals;Health;Health Personnel;Health Policy;Health Promotion;Health Resources;Health behavior;Healthcare;Heart Diseases;High Prevalence;Individual;Intervention;Kentucky;Life;Light;Lipids;Long-Term Effects;Maintenance;Mental Depression;Mental Health;Methods;Modality;Multimedia;Outcome;Patient Care;Patient Self-Report;Patients;Personal Satisfaction;Persons;Physical activity;Physically Handicapped;Policy Maker;Population;Poverty;Prevention;Quality of life;Randomized;Randomized Controlled Clinical Trials;Randomized Controlled Trials;Reporting;Research;Resources;Risk;Risk Factors;Risk Reduction;Rural;Self Care;Self Management;Skilled Nursing Facilities;Symptoms;Tablets;Technology;Testing;Time;United States Health Resources and Services Administration;Work;cardiovascular disorder risk;cardiovascular health;caregiver interventions;caregiving;clinically significant;depressive symptoms;design;digital;efficacy testing;evidence base;group intervention;health care availability;health disparity;high risk;improved;informal caregiver;innovation;intervention effect;intervention program;male;meetings;mortality;physical conditioning;prevent;primary caregiver;primary outcome;programs;psychological distress;rural area;social;socioeconomics;treatment as usual


application_id: 9234461
project_number: 5R21AI124081-02
project_title: Regulation of GC B Cells by Transcription Factor STAT3
administering_ic: NIAID
award_notice_date: 2017-02-24
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 124081
program_official: RICE, JEFFREY S
project_start_date: 2016-03-01
project_end_date: 2019-02-28
study_section: Cellular and Molecular Immunology - A Study Section[CMIA]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Germinal centers (GCs) are unique microenvironment that has proliferative B cells undergoing class switching somatic hypermuation and affinity maturation. Although alternative pathways exist GCs are the major source of long-lived antibody (Ab)-secreting plasma cells and memory B cells. Previous studies have demonstrated that SLE may develop as a result of enhanced GC activity. Spontaneous GC formation has been found in the lupus-prone mice. In addition active lupus patients have abnormal GC reactions and increased plasma cells. Therefore understanding signaling pathways that regulate the GC formation and GC B cell differentiation may identify novel targets for the successful intervention of SLE.  The signal transducer and activator of transcription factor 3 (STAT3) signaling pathway is critical for human B cells to differentiate into Ab-secreting plasma cells. Dysregulation of STAT3 pathway has also been implicated in the development of SLE. However the role of STAT3 in the GC B cell response has been controversial. A previous study has demonstrated that B cell-specific STAT3 deficient mice have lower T- dependent IgG response but display normal GC formation. Paradoxically GC is the major source of both memory B cells and long-lived plasma cells. One caveat of this study is that they only examined GC response at day 12. Our preliminary studies demonstrated that B cell-specific STAT-3 KO mice had significantly decreased GC formation GC B cells and Tfh cells in the later phase (days 21 and 28) but not in the early time point (days 7 and 12). Furthermore STAT3-deficient autoreactive B cells had defective autoAb responses and GC B cell differentiation upon immunization. We hypothesize that STAT3 signaling is essential for the maintenance of the GC formation and GC B cell differentiation. Two Aims are proposed to address this hypothesis. Aim 1 determines the mechanisms by which STAT3 signaling regulates the maintenance of the GC formation and GC B cell response. We will test the hypothesis that STAT3 signaling is required for the GC B cell survival. The specific stage of GC B cell differentiation that requires STAT3 signaling will be determined. Aim 2 examines whether B cell intrinsic STAT3 signaling is required for autoAb production and disease progression in lupus-prone MRL/lpr mouse model. In addition we will use anti-CD19 single chain variable fragment (scFv) miniAb to specifically deliver STAT3 siRNA into B cells in MRL/lpr mice. The therapeutic efficacy of this intervention will be determined. The overall goal of this proposal is to determine how STAT3 signaling regulates the GC formation and GC B cell response and whether ablation of STAT3 signaling specifically in autoreactive B cells provides benefit for lupus treatment.

project_terms:
Ablation;Address;Affinity;Antibodies;Antigens;Apoptotic;Autoantibodies;Autoantigens;Autoimmune Diseases;B Cell Proliferation;B cell differentiation;B-Cell Development;B-Lymphocytes;CD19 gene;CD4 Positive T Lymphocytes;Cell Culture System;Cell Maintenance;Cell Survival;Cells;Development;Disease Progression;Etiology;Goals;Helper-Inducer T-Lymphocyte;Human;Immunization;Immunoglobulin A;Immunoglobulin Class Switching;Immunoglobulin G;Immunoglobulin M;In Vitro;Inflammatory;Interleukin-6;Kidney;Kinetics;Knock-out;Knockout Mice;Lupus;Maintenance;Measures;Memory B-Lymphocyte;Messenger RNA;Molecular;Mus;Pathogenesis;Pathology;Pathway interactions;Patients;Phase;Phosphorylation;Plasma Cells;Play;Process;Production;Reaction;Regulation;Role;STAT protein;STAT1 protein;Serum;Signal Pathway;Signal Transduction;Small Interfering RNA;Source;Structure;Structure of germinal center of lymph node;Systemic Lupus Erythematosus;T-Cell Activation;Testing;Time;Transcript;Transcription Factor 3;Treatment Efficacy;autoreactive B cell;cytokine;differentiated B cell;extracellular;innovation;lupus prone mice;mouse model;novel;novel strategies;plasma cell differentiation;public health relevance;response;successful intervention;systemic autoimmune disease;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This study will determine the cellular and molecular mechanisms by which STAT3 signaling pathway regulates the germinal center formation and germinal center B cell response. The successful completion of this study may provide an innovative approach for autoimmune disease therapy such as systemic lupus erythematosus (SLE).


application_id: 9233902
project_number: 5R21AI119557-02
project_title: Elucidating the Biogenesis of the Yersinia pestis Containing Vacuole
administering_ic: NIAID
award_notice_date: 2017-02-21
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 119557
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2016-03-01
project_end_date: 2019-02-28
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)S]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis is a facultative intracellular pathogen that causes the disease known as plague. Growing evidence indicates that intracellular growth in macrophages is important for Y. pestis virulence. Upon phagocytosis Y. pestis alters the maturation of the phagosome to generate a protective compartment within the cell known as the Yersinia containing vacuole (YCV). Key steps in the generation of the YCV include inhibition of YCV acidification expansion into a spacious vacuole and acquisition of the autophagic markers. However the mechanisms used by the bacterium to subvert the normal phagosome maturation process and generate the YCV have not been defined. Recently we have identified a subset of host Rab GTPases that are required for Y. pestis to survive within macrophages. Because Rab proteins are key mediators of vesicular trafficking phagosome maturation and autophagy we hypothesize that these GTPases are required by Y. pestis to subvert phagosome maturation and generate the YCV thus protecting the bacterium from macrophage clearance. As Rab proteins mediate many aspects of vesicular trafficking through direct interactions with specific organelles and recruitment of effector proteins in Aim 1 we will determine if Rab GTPase required for Y. pestis intracellular survival are specifically recruited to the YCV. In Aim 2 we will determine the contribution of individual Rab proteins on the biogenesis of the YCV. These studies will be the first to define the contribution of host Rab GTPases to the formation of the YCV. Ultimately understanding the YCV biogenesis process will enable us to identify Y. pestis pathogenicity factors that contribute to intracellular survival.

project_terms:
AGFG1 gene;Acute;Autophagocytosis;Autophagosome;Bacteria;Biogenesis;Bubonic Plague;Cells;Comprehension;Confocal Microscopy;Data;Development;Disease;Electron Microscopy;Exclusion;Generations;Goals;Growth;Guanosine Triphosphate Phosphohydrolases;Immune Evasion;Individual;Infection;Integration Host Factors;Killings;Lysosomes;Mediating;Mediator of activation protein;Membrane;Molecular;Organelles;Pathogenesis;Phagocytosis;Phagolysosome;Phagosomes;Plague;Play;Process;Proteins;RNA Interference;Recombinant Proteins;Recruitment Activity;Role;Testing;Transmission Electron Microscopy;Vacuole;Virulence;Virulence Factors;Work;Yersinia;Yersinia pestis;base;combat;defined contribution;design;human disease;improved;knock-down;macrophage;novel therapeutic intervention;novel vaccines;pathogen;public health relevance;rab GTP-Binding Proteins;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Yersinia pestis is the causative agent of plague an acute human disease and potential bioweapon. The work proposed here will define the role of host Rab GTPases in biogenesis of an intracellular niche which protects Y. pestis from macrophage killing. Understanding the interactions between Y. pestis and macrophages will provide a broader understanding of Y. pestis pathogenesis which may impact the design of new vaccine and therapeutic approaches to combat plague infections.


application_id: 9233778
project_number: 5R01AA024405-03
project_title: SAM Deficiency Mediated Epigenetic Mechanisms in Alcohol induced Immunosuppression
administering_ic: NIAAA
award_notice_date: 2017-03-02
application_type: 5
activity_code: R01
ic: AA
serial_number: 024405
program_official: WANG, JOE
project_start_date: 2015-03-10
project_end_date: 2020-02-29
study_section: ZAA1-GG(50)P
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-03-01
project_abstract:
CD4+ T cell depletion is a major component of the multiple detrimental effects of chronic alcoholconsumption on the immune system. Chronic alcohol abuse leads to abnormal S-adenosylmethionine (SAM)metabolism and decreased hepatic SAM levels. Our earlier work in CD4+ T cells has demonstrated thatethanol significantly decreases lymphocytic methionine adenosyltransferase (MAT II) expression and activitywith resultant SAM deficiency and also increases activation-induced Fas-mediated apoptotic death. Notablyexogenous SAM supplementation restored intracellular SAM and prevented apoptotic signaling and death inethanol treated CD4+ T cells. These data not only showed a causal role for SAM deficiency in ethanolmediated apoptotic death but also provided the proof-of-concept for SAM therapy in preventing alcoholinduced CD4+ T cell depletion and immune suppression. SAM functions as the critical methyl donor duringepigenetic regulation leading to enzymatic modification of histones and DNA cytosine residues. Our recentwork on ethanol treated primary human CD4+ T cells in vitro as well as CD4+ T cells obtained from alcoholicpatients has provided convincing preliminary data showing that ethanol exposure can cause transcriptionallypermissive modifications in histones associated with the FasL promoter. These histone modificationsenhance transcriptional activation of the FasL promoter resulting in increased mRNA expression apoptoticsignaling and cell death. The overall objective of this proposal is to systematically examine genome wide aswell as gene specific (promoter associated) histone and DNA modifications involved in alcohol-mediatedapoptotic signaling and death in CD4+ T cells. We expect that the results of our study will provide criticalmolecular insights in the alcohol-induced immunotoxicity of CD4+ T cells. We predict that results from thisresearch will also provide important insights into immune dysfunction/CD4+ T cell loss in alcohol consumingHIV-infected patients. The specific aims of this translational proposal investigating the epigeneticmechanisms involved in aberrant apoptotic signaling and cell death of CD4+ T lymphocytes in alcoholicpatients are: Aim 1: Examine the effects of alcohol on cellular SAM levels global histone and DNAmodifications and apoptotic cell death in CD4+ T cells. Aim 2: Determine the gene specific (promoterassociated) histone and DNA modifications occurring in response to alcohol-mediated SAM deficiency thatimpact the expression of apoptotic genes relevant to CD4+ T cell survival.RELEVANCE (See instructions):Alcohol abuse continues to be a significant burden on the US healthcare system. The studies proposed herewill examine epigenetic modifications involved in alcohol-induced depletion of CD4+ T lymphocytes usingboth a genome-wide approach as well as a hypothesis-based candidate gene approach. The data obtainedfrom these studies will yield mechanistic insights underlying alcohol induced immune suppression and howalcohol may further depress immune function in HIV-infected patients.

project_terms:
Alcohol abuse;Alcohol consumption;Alcohols;Apoptotic;CD4 Positive T Lymphocytes;Candidate Disease Gene;Cell Death;Cell Survival;Cessation of life;Chronic;Clinical;Cytosine;DNA;DNA Modification Process;Data;Depressed mood;Epigenetic Process;Ethanol;Gene Expression;Genes;Genetic Transcription;HIV;Healthcare Systems;Hepatic;Histones;Human;Immune System Diseases;Immune System and Related Disorders;Immune system;In Vitro;Lymphocyte;Mass Spectrum Analysis;Mediating;Metabolism;Modification;Molecular;Natural immunosuppression;Patients;Proteomics;Research;Role;S-Adenosylmethionine;Signal Transduction;Supplementation;Transcriptional Activation;Work;alcohol abuser;alcohol effect;alcohol exposure;alcohol response;base;chronic alcohol ingestion;epigenetic regulation;genome-wide;histone modification;immune function;immunotoxicity;insight;mRNA Expression;methionine adenosyltransferase;permissiveness;prevent;problem drinker;promoter


application_id: 9233200
project_number: 5R01NS065842-10
administering_ic: NINDS
award_notice_date: 2017-03-07
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 065842
program_official: KOENIG, JAMES I
project_start_date: 2010-04-01
project_end_date: 2020-03-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
project_title:
Alpha5Beta1 Integrin inhibition as a Profound Blood-Brain Barrier Stabilizing Neuroprotective Stroke Therapy

project_abstract:
DESCRIPTION (provided by applicant): Although stroke is the fourth leading cause of death in the U.S. the current treatment strategy of thrombolysis for the majority of strokes due to a blood clot (ischemic) has mixed results. Thus there is an urgent need for new and better stroke therapies. We have previously demonstrated that the domain V protein fragment of the brain extracellular matrix component perlecan is both neuroprotective and neuroreparative after ischemic stroke by interaction with the brain endothelial cell receptor 51 integrin. Intriguingy preliminary results now suggest that mice with an endothelial selective deletion of 51 integrinare profoundly resistant to experimental ischemic stroke; they show little to no signs of brain injury. Furthermore inhibition of the 51 integrin with ATN-161 or its more potent isoform Ac-PhScN-NH2 conveys nearly identical resistance to stroke injury in wild type mice. This may occur via stabilization of the blood-brain barrier through increased function of the brain endothelial cell tight junction protein claudin-5 which in turn minimizes vasogenic edema inflammation and injury. Therefore we hypothesize that endothelial cell 51 integrin could be a particularly effective therapeutic target for stroke. In this application we propose the followig specific aims: 1. Determine the effect of endothelial cell selective 51 integrin deletion on experimental ischemic stroke 2. Determine the potential of the 51 integrin as a therapeutic target in experimental ischemic stroke and 3. Determine in mechanistic detail the role of 51 integrin in modulating blood-brain barrier integrity and subsequent resistance to ischemic stroke. We will use several novel genetically modified mice (5 integrin endothelial cell specific knockdown mice claudin5 eGFP tagged mice) and newly characterized 51 integrin inhibitors in experimental stroke models and in vitro endothelial cell barrier assays. We expect to demonstrate that suppression or inhibition of 51 integrin in endothelial cells affords significnt blood-brain barrier-mediated resistance to experimental ischemic stroke supporting our long-term goal of developing 51 integrin as a novel human stroke therapeutic target.

project_terms:
Anatomy;Antineoplastic Agents;Apoptosis;Biochemical;Biological Assay;Blood - brain barrier anatomy;Blood coagulation;Blood flow;Brain;Brain Injuries;Cause of Death;Clinical;Dose;Endothelial Cells;Extracellular Matrix;Genetic;Glucose;Goals;Histology;Human;Immunohistochemistry;In Vitro;Infarction;Inflammation;Injury;Integrin Inhibition;Integrin alpha5;Integrin alpha5beta1;Integrins;Ischemia;Ischemic Brain Injury;Ischemic Stroke;Knock-out;Knockout Mice;Label;Link;Magnetic Resonance Imaging;Mediating;Methods;Middle Cerebral Artery Occlusion;Modeling;Morbidity - disease rate;Motor;Mus;Oxygen;Peptides;Permeability;Protein Fragment;Protein Isoforms;Proteins;Proteoglycan;Receptor Cell;Receptor Inhibition;Recovery of Function;Resistance;Role;Signal Transduction;Testing;Therapeutic;Tight Junctions;Time;Treatment Efficacy;Wild Type Mouse;analog;brain endothelial cell;cancer clinical trial;cell injury;cell type;cerebrovascular;deprivation;experience;in vivo;inhibitor/antagonist;innovation;knock-down;mouse model;novel;novel therapeutic intervention;perlecan;post stroke;prevent;public health relevance;receptor;repaired;response to brain injury;stroke;stroke therapy;therapeutic target;thrombolysis;treatment strategy;vasogenic edema

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although stroke is the fourth leading cause of death in the U.S. current treatment options are limited in their application and efficacy. Towards that end we have identified a novel component of the brain's injury response derived from the brain's extracellular matrix which appears to protect cells from injury and help the brain to repair itself We further showed that this component termed perlecan domain V exerted its beneficial effects through interaction with the 51 integrin receptor on brain vascular (endothelial) cells Preliminary results now suggest that inhibition of this receptor profoundly protects the brain fromstroke injury and may do so by preventing breakdown of the blood-brain barrier. Therefore we propose to determine the therapeutic efficacy and mechanism(s) of action of targeting the 51 integrin in experimental ischemic stroke with the long term goal of developing better stroke therapies.


application_id: 9233072
project_number: 5R01DE024509-04
project_title: Filifactor alocis interactions with neutrophils
administering_ic: NIDCR
award_notice_date: 2017-02-16
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DE
serial_number: 024509
program_official: LUNSFORD, DWAYNE
project_start_date: 2014-07-01
project_end_date: 2019-03-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8652094
contact_pi: URIARTE, SILVIA M
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Abstract Periodontitis is a microbial-induced chronic inflammatory disease that affects the gingival tissues supporting the tooth. With the development of high-throughput sequencing technologies and their application to the oral microbiota several newly appreciated organisms have become recognized as associated with periodontal lesions. Among these is the Gram-positive anaerobic rod Filifactor alocis which is present in high numbers in periodontal disease sites compared to healthy sites. However association does not establish causality and the challenge now is to determine the potential pathogenicity of F. alocis. Chronic inflammatory infectious diseases such as periodontitis can occur because the pathogens are able to evade or disable the innate immune system. Neutrophils are a major component of the innate host response and the outcome of the interaction between periodontal pathogens and neutrophils is a key determinant of oral health status. An understanding of both microbial and host factors is therefore essential to increase our knowledge of the periodontal disease process. The current proposal will test the hypothesis that Filifactor alocis modulates neutrophil functional responses as an immune evasion strategy to avoid killing and promote inflammation. We will test our hypothesis by the following specific aims: Aim 1: To characterize neutrophil respiratory burst response to F. alocis challenge. The goal of this aim will be to test the hypothesis that F. alocis stimulation causes dysfunction of select neutrophil responses and thus compromises bacterial killing. Aim 2: To characterize the neutrophil oxygen-independent antimicrobial response to F. alocis challenge. The goal of this aim will be to test the hypothesis that F. alocis will modulate neutrophil degranulation and thus subvert neutrophil antimicrobial mechanisms. Aim 3: To determine the effect of F. alocis on neutrophil recruitment and activation in an animal model. The goal of this aim will be to test the hypothesis that F. alocis infection will stimulate neutrophil recruitment activation and matrix metalloproteinases release to promote inflammation in vivo. The current project is a collaborative effort from a new/early stage investigator with expertise in neutrophil biology and inflammation (Dr. Uriarte) and an expert in the field of oral pathogens and host cell responses (Dr. Lamont). The proposed collaborative efforts offer an innovative and strong framework to study the interaction between F. alocis and neutrophils. Furthermore the data generated from this application are a necessary component of the information that will be required to allow the development of novel therapeutic strategies for controlling periodontal disease.

project_terms:
Adult;Affect;Anaerobic Bacteria;Animal Model;Bacteria;Bacterial Infections;Biology;Cells;Chronic;Communicable Diseases;Cytoplasmic Granules;Data;Development;Diagnostic;Disease;Enzymes;Etiology;Exocytosis;Functional disorder;Future;Gingiva;Goals;Health;Health Status;High-Throughput Nucleotide Sequencing;Human;Immune;Immune Evasion;Immune response;In Vitro;Infection;Inflammation;Inflammatory;Innate Immune System;Integration Host Factors;Intention;Killings;Knockout Mice;Knowledge;Lesion;Leukocytes;Maintenance;Matrix Metalloproteinases;Modeling;Mus;Neutrophil Activation;Neutrophil Infiltration;Oral;Oral health;Organism;Outcome;Oxygen;Particulate;Pathogenesis;Pathogenicity;Periodontal Diseases;Periodontitis;Phagosomes;Population;Porphyromonas gingivalis;Process;Recruitment Activity;Research;Research Personnel;Respiratory Burst;Role;Site;Stimulus;TLR2 gene;Technology;Testing;Tissues;Tooth structure;United States;antimicrobial;combat;in vivo;innovation;microbial;microbial host;microbiota;neutrophil;novel therapeutic intervention;novel therapeutics;oral bacteria;oral pathogen;pathogen;pathogenic bacteria;public health relevance;response;retinal rods;subcutaneous;synergism;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Project Narrative Periodontal disease is an inflammatory condition induced by oral pathogenic bacteria that affects over half of the adult population in theUnited States. Oral health status is maintained by the presence of white blood cells which are involved in killing the oral bacteria that cause periodontal disease. In the current study we propose to define the interaction between white blood cells and a newly appreciated bacterium which has been proposed as a diagnostic indicator of periodontal disease; with the intention of filling a significant gap in the understanding of which factors contribute to periodontal disease.


application_id: 9232302
project_number: 1R15GM117534-01A1
project_title: Sympathetic Regulation of Inflammation from Sleep Fragmentation
administering_ic: NIGMS
award_notice_date: 2016-09-21
opportunity_number: PA-13-313
application_type: 1
activity_code: R15
ic: GM
serial_number: 117534
suffix: A1
program_official: SESMA, MICHAEL A
project_start_date: 2016-09-21
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1 MDCN-R (86)]
contact_pi_person_id: 10465930
contact_pi: ASHLEY, NOAH TODD
other_pis: Not Applicable
congressional_district: 02
department: BIOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
project_abstract:
Primary sleep abnormalities (insomnia shift work and obstructive sleep apnea (OSA)) promote aninflammatory environment and are associated with the development of cardiovascular and metabolic disease.However the mechanisms underlying these relationships are poorly understood. The proposed researchexamines hormonal and vascular mechanisms that underlie the inflammatory response to sleep loss usinggenetic and pharmacological approaches in mice. Sleep loss can activate the sympathetic nervous system(SNS) leading to an increase in catecholamines (epinephrine and norepinephrine) as well as elevate bloodpressure but it is unspecified how modulation of these specific components affects inflammatory responses toexperimental sleep fragmentation (SF). Aim 1 will examine whether catecholamines play a role in regulatingthe onset of SF-induced inflammation and the activation of microglia an important contributor toneuroinflammation. Spefically mice will receive chemical sympathectomy and then subjected to acute andchronic SF. Pro- and antiinflammatory gene and protein expression will be assessed using RT-PCR andmultiplex Luminex protein arrays respectively. Immunocytochemistry will be used to assess microgliaactivation. These findings will be validated through pharmacological inhibition of alpha and beta adrenergicreceptors. Instead of a classic anti-inflammatory effect it is predicted that catecholamines will potentiate SF-induced inflammation. Aim 2 will test whether manipulation of blood pressure alters inflammatory responses tovascular sheer stress by comparing the effects of pharmacological blockade of the sympathetic and renin-angiontensin system upon SD-induced inflammation. Taken together the proposed research will assess theimportance of the sympathetic response in mediating inflammation during sleep loss and provide uniquetraining opportunities for undergraduates interested in conducting biomedical research in endocrinologycardiovascular physiology and the neurosciences.

project_terms:
Acute;Adipose tissue;Adult;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Biomedical Research;Blood Pressure;Blood Vessels;Brain;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Catecholamines;Chemical Sympathectomy;Child;Chronic;Cytokine Gene;Data;Development;Disease;E-Selectin;Endocrinology;Environment;Epidemiology;Epinephrine;Exhibits;Gene Expression;Generations;Genetic;Habits;Health;Heart;Hormonal;Hypothalamic structure;Immunohistochemistry;Immunology;Incidence;Inflammation;Inflammatory;Inflammatory Response;Interleukin-1;Lead;Link;Measurement;Mediating;Metabolic;Metabolic Diseases;Metabolic Syndrome X;Microglia;Morbidity - disease rate;Morphology;Mus;Neurobiology;Neurosciences;Norepinephrine;Obesity;Obstructive Sleep Apnea;Outcome;Patients;Peripheral;Phenotype;Play;Prevalence;Protein Array;Proteomics;Regulation;Renin;Renin-Angiotensin System;Research;Reverse Transcriptase Polymerase Chain Reaction;Role;Shift-Work Sleep Disorder;Sleep;Sleep Apnea Syndromes;Sleep Disorders;Sleep Fragmentations;Sleeplessness;Societies;Stress;Sympathetic Nervous System;System;Technology;Testing;Tissues;Vascular Cell Adhesion Molecule-1;beta-adrenergic receptor;blood pressure regulation;cytokine;immunocytochemistry;interest;mRNA Expression;neuroinflammation;novel therapeutic intervention;novel therapeutics;prevent;protein expression;research study;response;shear stress;shift work;sleep abnormalities;training opportunity;undergraduate student

public_health_relevance:
Poor sleep habits and sleep abnormalities caused by insomnia shift work and sleep-disordered breathing arebecoming more prevalent in modern society. Disordered sleep promotes inflammation which is a commonmechanism for the development of cardiovascular and metabolic diseases. Understanding how thesympathetic response contributes to the development of inflammation during sleep loss could lead to noveltherapeutic interventions for treating inflammation-dependent disorders such as cardiovascular disease.


application_id: 9232144
project_number: 5K08DK102542-02
project_title: Nephritogenic autoantibodies in systemic lupus
administering_ic: NIDDK
award_notice_date: 2017-01-25
opportunity_number: PA-14-046
application_type: 5
activity_code: K08
ic: DK
serial_number: 102542
program_official: RANKIN, TRACY L
project_start_date: 2016-02-25
project_end_date: 2021-02-24
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 11177796
contact_pi: CASTER, DAWN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Actins;Address;Affect;American;Animal Model;Annexins;Antibodies;Antigen Targeting;Antigen-Antibody Complex;Antinuclear Antibodies;Attention;Autoantibodies;Autoimmune Diseases;Award;Biological Markers;Cell physiology;Cells;Clinical;Cytoskeleton;Data;Deposition;Development;Development Plans;Diagnosis;Dialysis procedure;Discipline;Disease;End stage renal failure;Evaluation;Filtration;Functional disorder;Goals;Histopathology;Human;Immunoglobulin G;Impairment;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injury;K-Series Research Career Programs;Kidney;Kidney Failure;Knowledge;Lead;Life;Lupus;Lupus Nephritis;Membranous Glomerulonephritis;Mentors;Mentorship;Nucleosomes;Pathogenesis;Pathogenicity;Patients;Physicians;Prognostic Marker;Proteins;Proteinuria;Publications;Renal glomerular disease;Research;Role;Scientist;Serum;Systemic Lupus Erythematosus;Testing;Therapeutic immunosuppression;Time;Tissues;Training;Treatment Protocols;Validation;base;career;career development;diagnostic biomarker;disease diagnosis;ds-DNA;experience;experimental study;improved;improved outcome;injured;lupus prone mice;mesangial cell;moesin;mouse model;novel diagnostics;podocyte;programs;public health relevance;skills;treatment response


application_id: 9232118
project_number: 5K23DC014074-03
project_title: Promoting Early Diagnosis of Congenital Hearing Loss through Patient Navigation
administering_ic: NIDCD
award_notice_date: 2017-02-23
opportunity_number: PA-14-049
application_type: 5
activity_code: K23
ic: DC
serial_number: 014074
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2015-03-01
project_end_date: 2019-02-28
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 11512687
contact_pi: BUSH, MATTHEW LEE
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): With the incidence of approximately 1.5 per 1000 births pediatric hearing loss is the most common neonatal sensory disorder in the United States. During the early years of life the sense of hearing is vital for the optimal development o speech language and cognition. Deafness in early childhood can result in lifelong learning delay and disability leading to adulthood challenges in education employment and social life. The economic costs of hearing loss and impaired language development are substantial. Early identification and intervention can prevent these adverse economic educational and social consequences. National standards dictate that infants who are deaf or hard of hearing should be diagnosed by 3 months of age and subsequent intervention services should be initiated no later than 6 months of age. Unfortunately 24% of infants have no diagnostic testing after abnormal infant screening and 29% of children with hearing loss are not enrolled in intervention services.1 Children from rural Appalachia and economically depressed regions have poor adherence to follow-up testing and are often delayed in diagnosis and treatment of pediatric hearing loss.2 The process of obtaining timely hearing health care for infants is complex and many factors such as communication breakdowns lack of decisional support and poor care coordination contribute to the disparity. Early infant hearing detection and intervention (EHDI) i coordinated on a state level and in spite of multiple initiatives to decrease EHDI non-adherence there is no established method to address this problem. In fact there is no evidence-based research that addresses the effectiveness of initiatives designed to decrease non-adherence for diagnosis or intervention.3 The research proposed in this application seeks to rectify this health disparity by addressing non-adherence and delays in the EHDI process during the first year of life through a novel intervention involving a patient navigator program (PNP). Navigators are trained healthcare workers who educate patients on health conditions and healthcare systems and expeditiously facilitate adherence to complex healthcare. PNPs have successfully decreased non- adherence to clinical testing and treatment in other health areas (e.g. cancer) but have not been utilized in the EHDI field. The hypothesis of this study is that a PNP will significantly decrease non-adherence to and timing of diagnostic audiological testing and intervention for infant hearing loss. The specific aims are to 1) examine the efficacy of a PNP to decrease non-adherence to and timing of recommended infant audiological testing within 3 months after birth in Appalachian and non-Appalachian participants 2) assess the efficacy of a PNP to decrease non-adherence to and timing of hearing aid fitting in infants diagnosed with hearing loss and 3) determine the maternal socioeconomic educational demographic and infant factors involved in non- adherence and delays to testing and treatment. We will accomplish Aim 1 by enrolling mother-child dyads in which the child fails newborn hearing screening into a randomized prospective study. The participants will be stratified into Appalachian and non-Appalachian based on county of residence and then within each stratum the subjects will be randomized into either the patient navigator group or the standard of care group. The navigator group will have weekly phone contact with a patient navigator after birth while the control group will receive the standard of care only and will have no contact with a navigator. Non-adherence to obtain audiological outpatient diagnostic testing before 3 months after birth (Aim 1) will be the primary outcome measure. Infants identified with hearing loss at our institution will be enrolled in Aim 2 and randomized into a patient navigator group or standard of care group similar to Aim 1. Non-adherence with fitting of hearing aids before 6 months of age will be the primary outcome for Aim 2. Secondary outcomes will include timing of diagnostic testing after birth (Aim 1) and the timing of hearing aid fitting after diagnosis (Aim 2. Aim 3 will characterize maternal and infant factors in non-adherence. The candidate is a clinician scientist at the University of Kentucky in the Department of Otolaryngology who has demonstrated commitment to a career in clinical and translational research. The mentors in this application Nancy Schoenberg Ph.D. Karl White Ph.D. Richard Kryscio Ph.D. will provide balanced training and guidance in the areas of health disparity infant hearing loss and intervention initiatives and clinical research design and implementation. The overall goal of thisK23 award is to provide the candidate with research and training activities that are focused on expediting diagnosis and treatment of infant hearing loss in the setting of health disparity. The training will expand the candidate's knowledge and experience with pediatric hearing health disparities research EHDI research and patient navigator integration and clinical trial design and analysis. The candidate is uniquely poised to investigate methods to expedite rural congenital hearing loss diagnosis and intervention. This application is intended to result in a research portfolio including subsequent R01 funding devoted to expediting hearing loss intervention in children who face barriers to care. The overall career goal of the candidate is to become an independently funded surgeon scientist focused on transforming the delivery of effective multidisciplinary hearing interventions. These goals are in line with NIH and NIDCD priority areas of improving diagnosis and treatment of hearing loss and developing evidence-based approaches that increase awareness access and affordability for those experiencing health disparities.

project_terms:
Address;Adherence;Adult;Affect;Age-Months;Appalachian Region;Area;Auditory;Awareness;Behavioral;Birth;Caring;Child;Childhood;Clinical Research;Clinical Treatment;Clinical Trials Design;Cognition;Communication;Complex;Congenital Disorders;Control Groups;County;Data;Deafness;Decision Making;Depressed mood;Detection;Development;Diagnosis;Diagnostic;Diagnostic tests;Doctor of Philosophy;Early Diagnosis;Early Intervention;Early identification;Economics;Education;Effectiveness;Employment;Enrollment;Face;Family;Funding;Goals;Health;Health Personnel;Health Services Accessibility;Healthcare;Healthcare Systems;Hearing;Hearing Aids;Hearing Impaired Persons;Hearing Tests;Incidence;Infant;Infant Care;Institution;Intervention;Intervention Studies;Joints;Kentucky;Knowledge;Language;Language Development;Learning;Life;Literature;Malignant Neoplasms;Medical;Mentored Patient-Oriented Research Career Development Award;Mentors;Methods;Mothers;National Institute on Deafness and Other Communication Disorders;Nature;Neonatal;Newborn Infant;Otolaryngology;Outcome;Outcome Measure;Outpatients;Parents;Participant;Patients;Phonation;Plant Roots;Process;Prospective Studies;Randomized;Recruitment Activity;Research;Research Activity;Research Design;Rural;Rural Health;Scientist;Sensory;Sensory Disorders;Services;Speech;Surgeon;Telephone;Testing;Therapeutic Intervention;Time;Training;Training Activity;Translational Research;Trust;United States;United States National Institutes of Health;Universities;base;career;design;disability;early childhood;economic cost;effective therapy;evidence base;experience;follow-up;health care disparity;health disparity;hearing impairment;hearing screening;improved;multidisciplinary;navigator intervention;novel;prevent;primary outcome;programs;public health relevance;research clinical testing;residence;rural healthcare;screening;secondary outcome;service intervention;social;socioeconomics;sound;standard care;standard of care;success;theories;therapy development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Hearing loss is the most common sensory congenital disorder and this condition is diagnosable and treatable. Children who are born with hearing loss must undergo several hearing tests to diagnose the condition and many families are delayed in receiving this testing or never obtain the necessary testing and treatment. This research evaluates a new method for helping children with hearing loss obtain timely care by using a patient navigator which is a trusted layperson who provides educational support for parents of these children by making a personal connection.


application_id: 9231040
project_number: 4R00AG044445-03
project_title: Involvement of myelin integrity in Alzheimer's disease pathogenesis
administering_ic: NIA
award_notice_date: 2016-04-28
opportunity_number: PA-11-197
application_type: 4
activity_code: R00
ic: AG
serial_number: 044445
program_official: OPANASHUK, LISA A
project_start_date: 2016-05-01
project_end_date: 2019-04-30
study_section: NSS
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This K99/R00 application provides career development training and a research plan to further the understanding of glial responses in white matter in the context of Alzheimer's disease (AD). The hypothesis to be tested is that a progressive loss of myelin integrity occurs in AD activating microglia towards a proinflammatory feed-forward loop which mediates hyperphosphorylation of the microtubule-associated protein tau and traditional AD pathology: neuritic plaques (NP) and neurofibrillary tangles (NFTs). Conventionally considered a disease of the CNS gray matter AD also has pronounced and progressive deterioration of cerebral white matter. Recent evidence suggests that changes in myelin integrity could be an early factor driving AD pathology through stimulation of inflammatory microglia activation and subsequent axonal damage. Extensive work has been done to understand the glial response in AD gray matter yet very little is known about microglia activation in AD white matter despite the fact that we and others have found a more robust activation of microglia and inflammatory response in AD white matter compared to gray matter. No studies have systematically and quantitatively examined myelin changes and inflammatory profiles as a function of disease progression. Our project will fill this gap by using human autopsy tissue and a mouse model that exhibits loss of myelin integrity to test our hypothesis. Our specific aims are: 1) Quantify the relationship between myelin integrity microglia activationproinflammatory cytokine levels and traditional measures of AD burden (NPs and NFTs) in the white matter of autopsy samples; 2) Determine if loss of myelin integrity induced by mutation in PLP in hTau mice will accelerate hyper-phosphorylated tau pathology and if this pathology can be rescued by suppressing the chronic neuroinflammation using a glia cytokine inhibitor. This project takes advantage of a strong scientific environment and extensive resources at the University of Kentucky including the Alzheimer's Disease Center clinically well-characterized autopsy cases that span the disease pathology continuum and renowned scientific expertise of an enthusiastic and committed mentoring team. A comprehensive training and career development plan has been developed for the K99 phase that includes further scientific training in oligodendrocyte/myelin biology and human neuropathology; formal coursework and participation in local national and international scientific meetings; evaluative meetings with th mentoring team; and activities designed to improve communication writing teaching and management skills. Overall there is an outstanding intellectual environment and access to relevant expertise in the applicant's project area multiple opportunities for career growth and substantial institutional commitment. This rich and supportive environment will enable a highly promising young scientist to further develop his research expertise pursue his structured training and career development plan and launch his career as an independent academic investigator.

project_terms:
Alzheimer's Disease;Amyloid beta-Protein Precursor;Animal Model;Area;Automobile Driving;Autopsy;Biochemistry;Brain;Brodmann's area;Central Nervous System Diseases;Cerebrum;Chronic;Clinical;Cognitive;Communication;Data;Deterioration;Development Plans;Diffusion Magnetic Resonance Imaging;Disease;Disease Progression;Educational process of instructing;Environment;Enzyme-Linked Immunosorbent Assay;Event;Exhibits;Genes;Genetic;Goals;Growth;Health;Human;Human Biology;Immunoblotting;Immunohistochemistry;Induced Mutation;Inflammation;Inflammatory;Inflammatory Response;Interleukin-1 beta;International;Kentucky;Late Onset Alzheimer Disease;MAPT gene;Measures;Medial;Mediating;Mental disorders;Mentors;Methods;Microglia;Mus;Mutation;Myelin;Myelin Proteins;Neocortex;Neuregulin 1;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Neurons;Oligodendroglia;Pathogenesis;Pathologic;Pathology;Pathway interactions;Phase;Phosphorylation;Research;Research Personnel;Research Project Grants;Resources;Role;Sampling;Scientist;Senile Plaques;Structure;Synapses;TNF gene;Temporal Lobe;Testing;Tissues;Training;Universities;Work;Writing;axon injury;beta-site APP cleaving enzyme 1;brain tissue;burden of illness;career;career development;collaborative environment;cytokine;design;digital;feeding;frontal lobe;genetic risk factor;gray matter;hTau Mice;human tissue;hyperphosphorylated tau;improved;inhibitor/antagonist;insight;lipid transport;meetings;mild cognitive impairment;mouse model;myelination;neuroinflammation;neuron loss;neuropathology;pre-clinical;response;skills;white matter;white matter change;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This research project will provide fundamental insights regarding the role of microglia dysregulated neuroinflammation and white matter integrity in the temporal onset of Alzheimer's disease. Recent data suggest white matter involvement in a variety of neurodegenerative and psychiatric disease. Therefore the understanding of oligodendrocyte - microglia - neuron interaction in Alzheimer's disease could have a broad impact on our understanding of cognitive health and disease.


application_id: 9230839
project_number: 5R01EY012716-18
project_title: Functional State of Developing Retinogeniculate Synapse
administering_ic: NEI
award_notice_date: 2017-03-06
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: EY
serial_number: 012716
program_official: GREENWELL, THOMAS
project_start_date: 2001-05-01
project_end_date: 2018-02-28
study_section: Special Emphasis Panel[ZRG1-IFCN-Q(02)M]
contact_pi_person_id: 1864719
contact_pi: GUIDO, WILLIAM
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We have developed a powerful mouse model to study visual circuit development in the dorsal lateral geniculate nucleus (dLGN) the thalamic relay of retinal information to the visual cortex. To date studies have focused largely on the retinogeniculate pathway and the refinement of connections between retinal ganglion cells and dLGN neurons. While many of the changes in retinogeniculate axon patterning and connectivity have been delineated information about two fundamental aspects of organization is still lacking. One relates to the cell- class specificity of connections between RGCs and dLGN cells and the other pertains to the source of connections to dLGN cells namely the wealth of input that arises from nonretinal projections. Both aspects are critical for a contemporary understanding of thalamic function which is to provide a faithful relay of retinal signals but at the same time to modulate the gain of transmission based on changes in behavioral state. The goals of this proposal are to assess how retinogeniculate refinement relates to class specific connections whether retinogeniculate refinement proceeds in a way that establishes separable parallel visual channels to determine when nonretinal projections develop in dLGN and to assess how such input coordinates with the innervation and refinement of the retinogeniculate pathway. To address these issues we will conduct anatomical electrophysiological and optogenetic experiments in transgenic mice that allow for the visualization and experimental isolation of specific cell types arising from the retina or from such nonretinal sources as layer VI of visual cortex the thalamic reticular nucleus and cholinergic nuclei of the brainstem. These studies willprovide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity.

project_terms:
3-Dimensional;Address;Adopted;Age;Anatomy;Architecture;Axon;Behavioral;Biological Models;Brain;Brain Stem;Cell Nucleus;Cells;Cholera Toxin Protomer B;Deafferentation procedure;Development;Disease;Dorsal;Electrophysiology (science);Event;Exhibits;Eye;Felis catus;Genetic;Goals;Imagery;In Vitro;Injection of therapeutic agent;Injury;Interneurons;Knowledge;Label;Lateral Geniculate Body;Life;Light;Mus;Neurons;Optic Nerve;Pathway interactions;Pattern;Preparation;Retina;Retinal;Retinal Ganglion Cells;Rhodopsin;Signal Transduction;Slice;Source;Specificity;Synapses;Testing;Thalamic structure;Time;Transgenic Mice;Transgenic Organisms;Trees;Variant;Viral;Visual;Visual Cortex;base;biocytin;cell type;cholinergic;developmental disease/disorder;experimental study;field study;insight;loss of function;monocular;mouse model;mutant;nerve supply;nervous system disorder;optogenetics;postnatal;preference;public health relevance;reconstruction;response;retinal axon;retinal progenitor cell;retinogeniculate;synaptogenesis;transcription factor;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: These studies will provide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity. Knowledge gained from these studies will also have important implications for understanding and predicting how thalamic circuits involving retinal and nonretinal projections respond to disease or injury.


application_id: 9230475
project_number: 4R37AI052218-16
project_title: In Vitro Glycorandomization of Natural Products
administering_ic: NIAID
award_notice_date: 2017-02-03
opportunity_number: PA-11-260
application_type: 4
activity_code: R37
ic: AI
serial_number: 052218
program_official: DAVIS, MINDY I
project_start_date: 2002-06-03
project_end_date: 2022-05-31
study_section: NSS
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT OF THE RESEARCH PLAN The studies to be pursued under the proposed extension fall within three general areas: i) enzyme catalystengineering and modulation (theme 1); ii) selected platform applications (theme 2); and iii) a systematic studyof the impact of glycosylation on fundamental drug properties (theme 3). The key tenets of each are brieflydescribed below and parallel the consistently high level of significance and innovation reflected in past periodsof support. The overarching significance stems from the anticipated advancements of universal principles forenzyme catalyst engineering/modulation novel enabling strategies for synthesis and biosynthetic study uniqueprobes or leads of significance to diverse therapeutic areas and a potential new conceptual framework for thegeneral use of glycosylation in drug development. Anticipated drivers of innovation are both by design(particularly novel synthetic and assay strategies) and directed discovery (unprecedented glycosyltransferasemodulators and probes/leads with high potential to lead to new understanding in the fundamentals ofimmunomodulation and/or inflammation). Studies directed toward enzyme catalyst engineering and modulation (theme 1) will focus on comparing thedirected evolutionary paths among the structurally similar glycosyltransferases (GTs) OleD and OleI assessingthe transferability of beneficial mutations across OleD and OleI and identifying mutational hot spots within theatypical GTB-fold GT AmphD1. The comparative OleD/OleI studies will consist of: i) the evaluation of an OleILoki which contains the 5 key mutations of structurally conserved residues that led to OleD Loki; and ii) aparallel epPCR-directed evolution approach for increasing OleI proficiency/permissivity using the same screensand mutational strategy that led to the discovery of enhanced OleD progeny. Key outcomes of this comparativestudy will be a potential universal blueprint for improving the proficiency/promiscuity of most GTB-fold GTs andimproved GTs for select sugar-conjugation (D-Gal analogs) to support theme 3. The directed evolution ofAmphD1 (and parallel proposed structure elucidation and structure-based engineering) will also follow our OleDprecedent and offers both the potential to expand the universal GT engineering blueprint toward atypical GTsand to identify GT variants to dramatically simplify the targeted synthesis of the unique preclinical antifungal lead2-epi-amphotericin (theme 2). In addition we will pursue the mechanistic study of small molecule inhibitors andactivators identified via the ClNP-Glc-based HT screen - studies that hold high potential in the discovery of newparadigms for GT catalytic modulation that may extend to other enzyme families and/or have pharmacologicapplications. Finally while we remain enthusiastic about the uncharted frontier of enzyme modulation viacontrolled electrical fields such technically challenging experiments require the physical presence of both thematerials scientists and enzymologists and unfortunately our local collaborator (Prof. Hinds) recently relocatedto the University of Washington. Thus this has become a lower priority in the near term. Among the various selected platform applications (theme 2) we will direct the real-time NMR-based assaytoward key and novel late-stage biosynthetic transformations - specifically to understand the stepwiseaminopentose N-alkylation reactions en route to enediynes and indolocarbazoles and the key steps of enediyne-associated thiosugar biosynthesis. The main outcome of these studies will be the elucidation of what isanticipated to be (based on bioinformatics) novel enzyme-catalyzed chemistries. In addition we will continue theongoing studies discussed within the progress report (immunomodulatory studies with macrolide neoglycosidesanti-Mtb studies with spectinomycin neoglycosides and further advancing protein glycosylation studies) andinitiate new combined (neo)glycorandomization diversification efforts toward a prioritized list of additional targets.Specifically we seek to generate and evaluate (neo)glycorandomized libraries of a third or fourth generation -lactam antibiotic (primary objective to broaden antibacterial scope) rapamycin (primary objectives to assessmechanistic modulation and potency) and daptomycin (primary objectives to improve formulation potencyand/or antibacterial scope). For all targets selected we have access to the necessary fundamental evaluativeactivity assays within my lab or via the Center of Pharmaceutical Research and Innovation (under mydirectorship) and these new initiatives hold promise for the discovery of new potential anti-infective anticancerand/or immunomodulatory probes/leads and for advancing new tools for biopharmaceutical development. As highlighted in the progress report we have also initiated arguably one of the first broad systematic studiesof the impact of glycosylation on fundamental drug properties (theme 3) the strategic design of which will probeboth the impact of the sugar and corresponding drug leaving group on key drug property principles. Thecorresponding in vitro and in vivo drug properties of the -glucosides will be evaluated by Vertex. In parallelProf. Leggas (co-I) will evaluate the in vitro and in vivo drug properties of a SN-38 10-O--glycoside sugar variantseries from which the top 2-3 analogs will be selected for subsequent in vivo anticancer efficacy studies. Thesestudies are anticipated to reveal fundamental insights regarding the impact of the sugar drug and correspondingglycosidic bond as the basis of a potentially new conceptual framework for the general use of glycosylation as atransformative drug development tool.Program Director/Principal Investigator (Last First Middle): Thorson JonDETAILED BUDGET FOR INITIAL BUDGET PERIOD DIRECT COSTS ONLYFROM07/01/2016THROUGH06/30/2017List PERSONNEL (Applicant organization only)Use Cal Acad or Summer to Enter Months Devoted to ProjectEnter Dollar Amounts Requested (omit cents) for Salary Requested and Fringe BenefitsNAMEThorson JonLeggas MarkosZhang JianjunHughes RyanEckenrode JosephROLE ONPROJECTCal.MnthsAcad.MnthsSummerMnthsINST.BASESALARYSALARYREQUESTEDFRINGEBENEFITSPD/PI 2.40 183300 36660 9929Co-I 0.36 121097 3633 1093Postdoc 12 44803 44803 14656Grad Student 12 24000 24000 4524Grad Student 12 24000 24000 4524  133096 34726 167822TOTAL465894726594592852428524SUBTOTALSCONSULTANT COSTSEQUIPMENT (Itemize)SUPPLIES (Itemize by category)Tissue culture cell biology molecular biology biochemical chemical reagents waste disposalBioanalytical reagents/suppliesLC/MS/MS maintenanceAnimal costs107775TRAVELtravel to scientific meetings3000INPATIENT CARE COSTSOUTPATIENT CARE COSTSALTERATIONS AND RENOVATIONS (Itemize by category)OTHER EXPENSES (Itemize by category)graduate student tuition publication costs.16666CONSORTIUM/CONTRACTUAL COSTSDIRECT COSTSSUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD (Item 7a Face Page) $ 295263CONSORTIUM/CONTRACTUAL COSTSFACILITIES AND ADMINISTRATIVE COSTSTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD $ 295263PHS 398 (Rev. 08/12 Approved Through 8/31/2015) OMB No. 0925-0001 Page Form Page 4

project_terms:
Alkylation;Ambulatory Care;Amphotericin;Anabolism;Animals;Anti-Bacterial Agents;Anti-Infective Agents;Antifungal Agents;Area;Biochemical;Bioinformatics;Biological Assay;Biological Products;Budgets;Caring;Categories;Cellular biology;Chemicals;Chemistry;Comparative Study;Daptomycin;Development;Direct Costs;Directed Molecular Evolution;Engineering;Enzymes;Evaluation;Face;Facilities and Administrative Costs;Family;Formulation;Fringe Benefit;Generations;Glucosides;Glycosides;Hot Spot;In Vitro;Inflammation;Lead;Libraries;Macrolides;Maintenance;Molecular Biology;Monobactams;Mutation;Mycobacterium tuberculosis;Natural Products;Outcome;Outcome Study;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Postdoctoral Fellow;Principal Investigator;Progress Reports;Property;Protein Glycosylation;Publications;Reaction;Reagent;Refuse Disposal;Research;Route;SN-38;Scientist;Series;Sirolimus;Spectinomycin;Structure;Students;Therapeutic;Time;Travel;Universities;Variant;Wages;Washington;analog;base;catalyst;comparative;cost;design;drug development;efficacy study;experimental study;falls;frontier;glycosylation;glycosyltransferase;graduate student;immunoregulation;improved;in vivo;innovation;insight;liquid chromatography mass spectrometry;novel;permissiveness;pre-clinical;programs;small molecule inhibitor;stem;sugar;thiosugar;tissue culture;tool;tool development


application_id: 9230424
project_number: 5UM1HL113530-06
project_title: University of Louisville Regional Clinical Center for the CCTRN
administering_ic: NHLBI
award_notice_date: 2017-02-17
opportunity_number: RFA-HL-12-026
application_type: 5
activity_code: UM1
ic: HL
serial_number: 113530
program_official: EBERT, RAY F
project_start_date: 2012-03-22
project_end_date: 2019-02-28
study_section: ZHL1-CSR-O(F2)
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    The University of Louisville/Jewish Hospital has a remarkably vibrant basic and clinical research program in cardiovascular medicine particularly in the area of stem cells and patients with heart failure (HF) left ventricular assist devices (LVADs) and ischemic cardiomyopathy. A highly cohesive and collegial team of investigators from the Divisions of Cardiovascular Medicine and Thoracic and Cardiovascular Surgery has worked productively for many years in several multicenter trials with outstanding performance. This existing clinical infrastructure coupled with the strong preclinical research work conducted on cell-based therapies for several years provides a superb platform for participation in the CCTRN as a Regional Clinical Center. The ability of our Center to carry out Phase l/ll studies of stem cells is exemplified by our success i performing the first in-human study of c-kit+ cardiac stem cells in patients with HF (SCIPIO). The same investigators and the infrastructure that made SCIPIO possible will be leveraged for the CCTRN studies. Here we propose SENECA (StEm cell treatmeNt for End stage CArdiac failure) in which we will test the feasibility and safety (Aim 1) and efficacy (Aim 2) of intracoronary delivery of CD34+ cells or very small embryonic-like cells (VSELs) to patients with end-stage ischemic cardiomyopathy (ICM) following implantation of an LVAD. Our hypothesis is that cell therapy will promote repair and regeneration of the injured myocardium resulting in improved cardiac function functional capacity and overall quality of life and recovery of myocardial function to a degree that permits consideration of LVAD explantation. In Aim 3 we will identify patient characteristics and in vitro parameters of stem cell function that are associated with effectiveness (or lack thereof) of CD34+ cells and VSELs in improving LV function in vivo. SENECA will be the first study of VSELs in humans and the first controlled trial to test the effects of CD34+ cells in end-stage ischemic HF. Therefore the results will be entirely novel and may provide a new option for patients who currently have a dismal prognosis. Thus the potential impact of SENECA is considerable. No cell therapy study has ever been reported before in patients with LVADs and ICM although these are the very patients who need it the most. Therefore SENECA will address a major therapeutic gap in the management of cardiac patients. This trial has the potential to provide a novel clinical breakthrough in the treatment of end-stage ischemic heart disease.

project_terms:
Activities of Daily Living;Address;Affect;Area;Basic Science;CD34 gene;Cardiac;Cardiac Surgery procedures;Cardiovascular Surgical Procedures;Cardiovascular system;Cell Therapy;Cell physiology;Cells;Cellular biology;Characteristics;Clinical;Clinical Research;Collaborations;Coupled;Effectiveness;Embryo;Enrollment;Environment;Event;Faculty;Goals;Heart failure;Hospitals;Human;Human Resources;Implant;In Vitro;Institution;Letters;Life;Medicine;Motivation;Multicenter Trials;Myocardial;Myocardial Ischemia;Myocardium;Names;Natural regeneration;Patients;Performance;Personnel Staffing;Phase;Population;Positioning Attribute;Postdoctoral Fellow;Proto-Oncogene Protein c-kit;Quality of life;Recovery;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Stem cells;Testing;Therapeutic;Thoracic Surgical Procedures;Time;Universities;Work;base;clinical infrastructure;cohesion;control trial;follower of religion Jewish;human study;implantable device;implantation;improved;in vivo;injured;insight;ischemic cardiomyopathy;left ventricular assist device;member;novel;outcome forecast;phase 1 study;phase 2 study;phase 3 study;pre-clinical research;preclinical study;programs;repaired;safety and feasibility;stem cell population;stem cell therapy;success

public_health_relevance:
We have conducted preclinical studies of stem cells for several years. In 2009 we started SCIPIO the first in-human study of c-kit+ cardiac stem cells and one that demonstrates the ability of our Center to carry out Phase l/ll studies of cell therapy in humans effectively and successfully. This application builds on SCIPIO and on the superb program in advanced heart failure at Jewish Hospital. The results may pave the way for the use of novel cell-based therapies (CD34+cells and/or VSELs) in patients with ischemic cardiomyopathy.


application_id: 9230385
project_number: 5R01DE017680-10
project_title: Role of GSK3 in host inflammation
administering_ic: NIDCR
award_notice_date: 2017-03-01
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DE
serial_number: 017680
program_official: CHANDER, PREETHI
project_start_date: 2007-04-25
project_end_date: 2019-02-28
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The overall goal of this project is to elucidate interacting endogenous anti-inflammatory pathways that can be harnessed to suppress an over-exuberant host response to periodontal bacteria and other pathogens. Bacteria are initially recognized by Toll-like receptors (TLRs) and other pathogen recognition receptors expressed on innate cells. TLR interaction with microbe-specific molecular patterns induces the innate production of pro- inflammatory cytokines which direct the intensity and direction of the immune response leads to recruitment of leukocytes to the site of infection and the production of an arsenal of anti-bacterial molecules many of which have the potential to cause the collateral tissue damage that defines destructive inflammatory diseases. There are at least three endogenous anti-inflammatory pathways. The first life cycle of DE017680 focused on the in vitro elucidation of the PI3K/ AKT anti-inflammatory pathway the key role of GSK3b in this signaling cascade and the mechanisms by which this pathway regulates the expression of IFNb IL-1Ra IL-10 in innate cells in addition to controlling T cell development and proliferation. In addition o the PI3K/ AKT cascade this renewal will also consider the a7 nicotinic acetylcholine receptor-dependent cholinergic and the Wnt3a anti- inflammatory pathways. Crosstalk between these three pathways will be elucidated with particular attention paid to the pivotal role of the centra inflammatory mediator GSK3b in pathway convergence. While each pathway is efficacious in its own right therapeutic interventions that maximize the anti-inflammatory potential of convergent signaling events are likely to be particularly potent. To this end anti-inflammatory signaling events will be exploited using murine models of inflammation (sub-cutaneous chamber) and periodontitis (alveolar bone loss). Therefore this project will lay the groundwork for the development of novel approaches to the treatment of periodontitis and other inflammatory diseases and identify therapeutic targets that should be readily translatable.

project_terms:
Alveolar Bone Loss;Amplifiers;Anti-Bacterial Agents;Anti-Cholinergics;Anti-Inflammatory Agents;Anti-inflammatory;Attention;Bacteria;Bacterial Infections;Cardiovascular system;Cells;Cessation of life;Chronic;Communicable Diseases;Complex;Data;Dental Plaque;Development;Disease;Disease Progression;Event;Glycogen Synthase Kinases;Goals;Health Care Costs;Host Defense;Human;Immune;Immune response;In Vitro;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Innate Immune System;Interferon-beta;Interleukin-10;Invaded;Lead;Leukocytes;Life Cycle Stages;Lung diseases;Matrix Metalloproteinases;Mediating;Microbe;Modeling;Molecular;Mus;Natural Immunity;Nature;Nicotinic Receptors;PI3K/AKT;Pathogenicity;Pathology;Pathway interactions;Pattern;Pattern recognition receptor;Periodontal Diseases;Periodontitis;Pharmacologic Substance;Play;Porphyromonas gingivalis;Production;Recruitment Activity;Regulation;Role;Seminal;Signal Pathway;Signal Transduction;Site;T-Cell Development;TLR2 gene;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Tissues;Toll-like receptors;adaptive immune response;anakinra;beta catenin;cholinergic;controlled release;cytokine;driving force;in vivo;microbial;mouse model;novel;novel strategies;oral pathogen;pathogen;pathogenic bacteria;public health relevance;receptor;response;subcutaneous;therapeutic target;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  It is the host response to dental plaque that leads to the development of periodontitis one of the most common infectious diseases in humans that consumes   >$14 billion dollars in health costs in the U.S. per annum. We will identify overlapping events between several endogenous mechanisms of inflammatory suppression (the PI3K/AKT/GSK3b; cholinergic; and Wnt3a anti-inflammatory pathways); elucidate specific mechanisms that suppress pro-inflammatory cytokine production in response to bacterial infection; determine anti-inflammatory events that control the release of tissue degrading matrix metalloproteinases; and establish if we can exploit these anti-inflammatory pathways to reduce inflammation and periodontal disease progression in murine models. These data will identify novel potential therapeutic approaches to the control of destructive inflammation.


application_id: 9229414
project_number: 7R01CA194409-02
project_title: sEcad as a novel target and therapy for IGF-1R expressing tumors
administering_ic: NCI
award_notice_date: 2016-04-15
opportunity_number: PA-14-078
application_type: 7
activity_code: R01
ic: CA
serial_number: 194409
program_official: MUSZYNSKI, KAREN
project_start_date: 2015-09-01
project_end_date: 2020-08-31
study_section: Cancer Immunopathology and Immunotherapy Study Section[CII]
contact_pi_person_id: 7799129
contact_pi: BROUXHON, SABINE M
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Over the last decade the most significant revolutionary advances in breast oncology have been the FDAapproval of targeted therapies against the human epidermal growth factor receptors (HER1 and HER2) andtherapies for hormone-receptor-positive disease. In combination with adjuvant chemotherapy drugs such astrastuzumab (anti-HER2 antibody) or tamoxifen (hormone therapy) have significantly reduced relapses andincreased disease-free survival in patients with metastatic disease. However despite an initial positiveresponse the majority of patients exhibit resistance - rendering the therapy ineffective within one year oftreatment. Increased expression and hyperactivation of the insulin-like growth factor 1 receptor (IGF-1R) andits associated downstream signaling components (MAPK-PI3K/Akt/mTOR- IAP) have been implicated in thisde novo and acquired resistance. Therefore identification of novel targets and antineoplastic agents thatmodulate IGF-1R signaling is paramount. We have recently identified soluble E-cadherin termed sEcad as a novel oncogenic target that isselectively increased in human breast cancers. Additionally we have discovered that sEcad imparts itstumorigenic effects (enhances proliferation migration and invasion) by activating many of these resistancepathways including IGF-1R and downstream MAPK-PI3K/Akt/mTOR-IAP signaling. More importantly using apurified IGF-1R holoreceptor we are the first to discover that sEcad acts as a true ligand for IGF-1R and in thepresence of its natural ligand IGF-1 synergistically increases IGF-1R phosphorylation. Furthermore we haveevidence that sEcad synergizes with the high-affinity HER and IGF-1R ligands IGF1 and EGF to promotecancer cell proliferation migration and invasion in vitro and act as an oncogenic driver in xenograft tumors invivo. Therefore we propose that sEcad is a valid and innovative therapeutic target for breast cancer. Additionally we have recently tested region-specific antibodies against sEcad that successfully suppressedHER2+ and hormone-receptor positive breast cancers by directly inducing tumor cell death (apoptosis andnecrosis) via down-regulating the IGF-1R HER and MAPK-PI3K/Akt/mTOR-IAP axis. In trastuzumabresistant breast cancer xenografts (which endogenously overexpress IGF-1R) and MMTV-PyMT mice ourstudies demonstrate that targeted inhibition of sEcad successfully reduced tumor burden by inhibitingproliferation and inducing cell death. Consistent with the in vivo findings this targeted therapy inhibitedproliferation and directly induced apoptosis and necrosis in hormone-receptor-positive and trastuzumabresistant breast cancer cells without showing any off-target cytotoxic effects in normal cells. In this translational study we have assembled an outstanding research team to: 1) biochemically andbiophysically characterize the sEcad-IGF-1R interactions; 2) determine whether targeted inhibition of sEcadsuppresses IGF-1R expressing breast cancers in vitro and in vivo; 3) gain mechanistic insights into how theantibody functions to down-regulate the IGF-1R axis; and 4) perform rodent efficacy PK/PD studies andevaluation of off-target effects. Of note although monoclonal antibodies against IGF-1R have given mixed results in clinical trials theseanti-sEcad antibodies potentially represent a completely different class of IGF1R inhibitors with a very uniqueand innovative targeting mechanism.

public_health_relevance:
PROJECT NARRATIVEBreast cancer is the most common cancer in women with 1.7 million new cases in 2012 worldwide. Soluble E-cadherin a small protein produced by cancer cells in large quantities appears to enhance cancer growth andexpansion. In this R01 grant we will study the function of soluble E-cadherin in breast cancer development andhow it binds to a cancer growth promoting receptor IGF-1R. Additionally we will test the effectiveness of a newtherapy we developed against this soluble fragment in human cells and mouse models of breast cancer so asto understand whether IGF-1R is involved. We believe that our discovery will lead to a new therapy for humanbreast cancer.


application_id: 9226932
project_number: 1R21NS099781-01
project_title: Validation of a Point of Care Diagnostic for Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2016-09-19
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: NS
serial_number: 099781
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2016-09-30
project_end_date: 2018-08-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Traumatic brain injury (TBI) is a substantial health care issue affecting both civilian and militarypopulations. Although extremes of head injury are recognizable mild to moderate TBI (MMTBI) is moredifficult to diagnose leading to a need for the identification of circulating biomarkers of brain injury that mayfacilitate early identification. Using a rat model of TBI we identified a novel marker of neuronal injury visininlike protein 1 (VILIP-1) that is released into blood rapidly after injury. To facilitate rapid measurement ofcirculating VILIP-1 we developed a combined lateral flow device (LFD) that provides detection of the biomarkerin less than 20 min. Although initial testing in human TBI patients are promising there is a need for furthertesting in blood samples drawn clinically well characterized TBI patients soon after injury. The aim of thecurrent proposal is to further validate the use of our LFD as a point of care diagnostic for TBI using acombination of archived serum samples from normal control subjects as well as patients with systemictraumatic injuries but no TBI and subjects with mild to moderate TBI and whole blood samples from patientsbeing evaluated in the emergency department of Orlando Regional Medical Center. If successful theproposed studies will validate the use of our VILIP-1 LFD for rapid in field detection of MMTBI and will providethe preliminary data to support a larger clinical trial of the device that could ultimately benefit both civilian andmilitary populations.

project_terms:
Accident and Emergency department;Acute;Adult;Affect;Afghanistan;Archives;Biological Markers;Blinded;Blood;Blood specimen;Brain;Brain Injuries;Cerebrospinal Fluid;Clinical;Clinical Trials;Code;Cohort Studies;Color;Coma;Computers;Craniocerebral Trauma;Data;Databases;Detection;Devices;Diagnosis;Diffuse;Early identification;Enrollment;Enzymes;Filament;Fracture;Future;Healthcare;Hemorrhage;Hospitals;Hour;Human;Immunoassay;Injury;Iraq;Kentucky;Lateral;Link;Measurement;Measures;Medical center;Military Personnel;Modeling;Myelin Basic Proteins;Nature;Neuron-Specific Enolase;Neuronal Injury;Neurons;Operative Surgical Procedures;Patients;Phase;Population;Proteins;Rattus;Research;Sampling;Scanning;Serum;Specificity;Sports;TBI Patients;Temperature;Testing;Therapeutic;Time;Trauma patient;Traumatic Brain Injury;Traumatic injury;Universities;Use Effectiveness;Validation;Veterans;Visual;War;Whole Blood;X-Ray Computed Tomography;abstracting;blood-based biomarker;circulating biomarkers;controlled cortical impact;falls;injured;interest;male;mild traumatic brain injury;neurotrophic protein S100beta;novel marker;point of care;point-of-care diagnostics;prospective;screening;sensor;tomography;vehicular accident;visinin

public_health_relevance:
NarrativeTraumatic brain injury (TBI) is a substantial health care issue affecting both civilian and militarypopulations. Despite considerable research there remains a critical need for a biomarker test that canrapidly measure a maker of mild to moderate TBI (MMTBI) in blood or cerebrospinal fluid and provideidentification of patient during a clinically useful time frame. Preliminary and future studies described inthis proposal aim to test the usefulness of a lateral flow device (LFD) that quantifies visinin like protein1 (VILIP-1) a neuron specific Ca2+-sensor protein released into blood following TBI.


application_id: 9225184
project_number: 5R21CA191663-02
project_title: Common hTERT Promoter Mutations Represent a Novel Therapeutic Target
administering_ic: NCI
award_notice_date: 2017-02-02
opportunity_number: PAR-13-146
application_type: 5
activity_code: R21
ic: CA
serial_number: 191663
program_official: FU, YALI
project_start_date: 2016-02-15
project_end_date: 2018-09-30
study_section: ZCA1-SRB-X(O1)
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Telomerase reverse transcriptase (hTERT) is a catalytic subunit of the enzyme telomerase which is frequently overexpressed in human tumors. It has recently been shown that the hTERT promoter is commonly mutated in a malignant melanoma and glioblastoma (>75% of tumors). These mutations occur at four specific sites in a G-rich region which has been shown to form quadruplex DNA and to downregulate hTERT expression. We have shown that these mutations destabilize quadruplex-formation resulting in increased hTERT expression and cellular proliferation. Stabilization of the quadruplex structure with TMPYP4 reverses these changes. Treatment of cells in which the hTERT promoter is mutated with "strand-invading" oligonucleotides downregulates hTERT expression and dramatically inhibits the growth of transformed cells. This application will test the hypothesis tht stabilization of the mutated hTERT promoter quadruplex structure by sequence specific oligonucleotides will result in downregulation of hTERT and inhibition of growth by cells with the mutated sequence(s). The Specific Aims of this application are: 1. To characterize the gene and sequence specificity of oligonucleotides targeted to the mutated or wild type hTERT promoter sequences. 2. To characterize the potential synergy of strand invading hTERT promoter targeted  oligonucleotides with targeted agents and standard chemotherapy drugs. 3. To characterize the therapeutic potential of hTERT strand invading oligonucleotides in animal models alone and in conjunction with targeted therapies. The results of the proposed studies will have important clinical implications as inhibition of hTERT gene expression is relevant to a wide variety of tumor types. In addition the proposed experiments will provide important new information about the role of quadruplex-formation in the regulation of hTERT gene expression.

project_terms:
Animal Model;Binding;Biophysics;Catalytic Domain;Cell Proliferation;Cells;Chromosomal translocation;Clinical;Clinical Trials;Down-Regulation;Enzymes;Functional disorder;GTP-Binding Protein alpha Subunits Gs;Gene Expression;Gene Silencing;Genes;Genetic Transcription;Glioblastoma;Goals;Growth;Human;Invaded;Malignant - descriptor;Mutate;Mutation;Oligonucleotides;Patients;Pharmaceutical Preparations;Physiological;Play;RNA-Directed DNA Polymerase;Regulation;Role;Site;Specificity;Structure;Telomerase;Testing;Therapeutic;Transcriptional Regulation;analytical ultracentrifugation;cancer cell;cancer therapy;cell growth;cell transformation;chemotherapy;design;experience;experimental study;interest;malignant phenotype;melanoma;mutant;new therapeutic target;novel;overexpression;promoter;public health relevance;quadruplex DNA;synergism;targeted agent;targeted treatment;tumor;tumor growth

public_health_relevance:
PUBLIC HEALTH RELEVANCE   Telomerase is overexpressed in over 90% of human tumors. It represents a very attractive target for anticancer therapy. The recent discovery of "common mutations" in the hTERT promoter has suggested that quadruplex formation may play an important physiologic role in hTERT silencing. We have shown that the mutations destabilize quadruplex and that these changes can be reversed by sequence-specific strand-invading oligonucleotides. This approach allows the stabilization of mutated hTERT promoter sequences and the reversal of hTERT dysregulation. We believe that these observations suggest that inhibition of hTERT expression is a reasonable goal with considerable clinical potential.


application_id: 9223404
project_number: 1R03CA211835-01
project_title: Differential Abundance Methods for Large Heterogeneous-Featured Metabolomics Datasets
administering_ic: NCI
award_notice_date: 2016-09-14
opportunity_number: RFA-RM-15-021
application_type: 1
activity_code: R03
ic: CA
serial_number: 211835
program_official: SPALHOLZ, BARBARA A
project_start_date: 2016-09-14
project_end_date: 2017-08-31
study_section: Special Emphasis Panel[ZRG1 BST-U (50)]
contact_pi_person_id: 10631406
contact_pi: WANG, CHI
other_pis: FLIGHT, ROBERT MAXWELL
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryMetabolomics deals with the systematic identification and quantification of small molecules inbiological systems. Frequently metabolomics studies aim to identify those metabolites that havedifferential abundances between two or more conditions. However in the very large untargetedmetabolomics datasets being generated today there are often many detected metabolitefeatures that will be zero for a large fraction of samples in either/or both sample classescreating data sparsity. Previous work has been done to develop statistical methods capable oftesting for differential abundances in metabolomics datasets with high data sparsity (i.e. largefraction of zero values in the dataset). However these methods are not appropriate for datafrom matched pair experimental designs which are expected to become the standard asmetabolomics is applied to more and more human disease studies. Furthermore the currentlyavailable methods either make simplistic statistical assumptions or use the simplest method fornot making assumptions about the data available which are not necessarily appropriate. Inaddition peak assignment and correspondence ambiguities play a large role in the zero valuesand redundancy seen in these datasets. However no methods have been developed to directlyaddress these issues. In this proposal we will develop novel informatics and statistical methods that addressthese distinct issues seen in large heterogeneous featured metabolomics datasets: i) a fuzzyset-based algorithm method that addresses peak assignment and correspondence ambiguitiesand ii) a semi-parametric method to perform differential abundance analysis for metabolomicsdatasets with high data sparsity possibly non-normally distributed data and matched-pairsexperimental designs. We will use simulation studies to assess how well these new methodsaddress the aforementioned issues and how much they improve the power of differentialabundance analysis. Finally we will make these new methods available through Bioconductorpackages and a web-based service.

project_terms:
Accounting;Address;Algorithms;Attention;Bioconductor;Bioinformatics;Computing Methodologies;Data;Data Analyses;Data Set;Development;Disease;Experimental Designs;Galaxy;Goals;Individual;Informatics;Measurement;Metabolic;Methods;Modeling;Online Systems;Play;Probability;Programming Languages;Research Personnel;Role;Sampling;Scientist;Services;Specific qualifier value;Statistical Data Interpretation;Statistical Methods;Statistical Models;System;Technology;Testing;Time;Uncertainty;Weight;Work;Writing;base;biological systems;computerized data processing;design;distributed data;human disease;human subject;improved;innovation;metabolomics;novel;novel strategies;research study;simulation;small molecule;tool;treatment effect;user-friendly;web interface;web site

public_health_relevance:
Project NarrativeNew large metabolomics datasets have a variety of issues related to ambiguity in metaboliteassignment correspondence of measurements across samples and redundancy of information.We are developing new computational methods to address these issues and robustlydistinguish metabolomics features that change between disease and non-disease humansubjects.


application_id: 9222689
project_number: 5R01AG047297-03
project_title: Asthma in Older Adults: Identifying Phenotypes and Factors Impacting Outcomes
administering_ic: NIA
award_notice_date: 2017-01-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 047297
program_official: ZIEMAN, SUSAN
project_start_date: 2015-02-01
project_end_date: 2020-01-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 11844758
contact_pi: POLIVKA, BARBARA J
other_pis: FOLZ, RODNEY J
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Asthma is a common chronic inflammatory disorder of the distal airways characterized by recurring symptoms airway inflammation and reversible airflow constriction. It is considered a collection of various phenotypes (characteristics) instead
of a single disease. Currently there is no comprehensive phenotyping specific to older adults with asthma that considers multiple factors relevant to this population. Divergent asthma phenotypes and exposure to unique environmental triggers may affect asthma control in the elderly. In addition factors contributing to asthma quality of life in the elderly have not been wll explored. The aims of our study are to: (1) develop and systematically implement a phenotyping algorithm in older adults with asthma; (2) longitudinally investigate the effects of asthma phenotypes and volatile organic compounds (VOCs) exposures on asthma control in older adults with asthma; and (3) develop a predictive model for asthma quality of life for older adults with asthma. Sub-aims are to explore the impact on moving from community-based to congregate living settings (e. g assisted living) on the course of asthma in older adults and to identify barriers to successful asthma medication management. One hundred ninety participants 60 years of age or older will be enrolled. Inclusion criteria are: meet standard diagnostic criteri for asthma non-smokers have no other chronic respiratory diseases do not reside in a skilled nursing facility and have not recently had a major a medical illness. At baseline participants wil complete spirometry bronchodilator responsiveness fractional exhaled nitric oxide methacholine challenge (if not completed within past 5 years) allergic sensitization Immunoglobulin E (IgE) and sputum analysis as well as standardized questionnaires to assess asthma control quality of life knowledge and self-efficacy. Within 30 days an in-home environmental assessment will be conducted to obtain data on VOCs air particulates moisture temperature humidity pests and an asthma home environment checklist. At 9 and 18 months in-home data will be collected on participants' pulmonary status asthma control and asthma quality of life. At 9-months participants will also complete the measures of medication management. At 18-months we will conduct follow-up in-home environmental assessments collecting the same data we collected at baseline. Participants who have moved to congregate living facilities will be asked open-ended questions about their perception of the effects of the move on the course of their asthma. Using factor analysis we will perform a comprehensive phenotypic characterization that will include a wide range of demographics asthma-specific knowledge and self-efficacy and biomarkers. Predictive models for asthma control and asthma quality of life will be identified using generalized linear mixed-effects modeling. The findings of
this study will be used in future research to develop and test the efficacy of patient-centered interventions for older adults with asthma to improve asthma control and enhance quality of life.

project_terms:
4 year old;Acute;Address;Affect;Age;Age-Years;Air;Algorithms;Allergic;Area;Assisted Living Facilities;Asthma;Attention;Biological;Biological Markers;Biophysics;Bronchial Spasm;Bronchodilator Agents;Characteristics;Child;Chronic;Collection;Communities;Data;Diagnostic;Disease;Distal;Drug Interactions;Elderly;Emergency department visit;Enrollment;Environment;Environmental Exposure;Exhalation;Exposure to;Factor Analysis;Home environment;Hospitalization;Household Products;Humidity;IgE;Individual;Inflammatory;Intervention;Knowledge;Life Style;Living Arrangement;Longitudinal Studies;Lung;Lung diseases;Measures;Medical;Medication Management;Methods;Modeling;NIH Program Announcements;Nitric Oxide;Non-smoker;Outcome;Paint;Participant;Particulate;Patient Selection;Perception;Pesticides;Pharmaceutical Preparations;Pharmacology;Phenotype;Physicians;Population;Prevalence;Quality of life;Questionnaires;Research;Research Personnel;Residential Facilities;Self Efficacy;Skilled Nursing Facilities;Spirometry;Sputum;Standardization;Stress;Symptoms;Temperature;Testing;Therapeutic Intervention;Visit;age group;airway inflammation;asthmatic;base;constriction;demographics;efficacy testing;experience;follow-up;improved;inclusion criteria;interest;methacholine;mortality;patient oriented;predictive modeling;public health relevance;residence;response;volatile organic compound

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This study will develop a method of categorizing asthma in older adults longitudinally investigate the effects of these categorizations on asthma control and identify factors such as environmental exposures and type of living arrangements that impact asthma quality of life for older adults. As the population ages and the percentage of older adults with asthma increases the information obtained from this study is needed to develop and test patient-centered interventions that will improve asthma control and quality of life in older adults with asthma.


application_id: 9221363
project_number: 5R34MH106661-03
project_title: Systematically Adapted Delivery of the Family Check-Up in Underserved Communities
administering_ic: NIMH
award_notice_date: 2017-03-17
opportunity_number: RFA-MH-15-330
application_type: 5
activity_code: R34
ic: MH
serial_number: 106661
program_official: PINTELLO, DENISE
project_start_date: 2015-03-01
project_end_date: 2019-02-28
study_section: ZMH1-ERB-I(01)
contact_pi_person_id: 8804342
contact_pi: STUDTS, CHRISTINA RUTH
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): When disruptive behavior problems manifest in very young children the risk of later antisocial behaviors- including substance abuse school failure and criminality-escalates significantly. Evidence-based behavioral parent training (BPT) interventions have demonstrated efficacy and effectiveness in a range of settings in preventing the negative outcomes and costs associated with disruptive behavior problems. However the public health impact of these interventions has yet to be realized in part due to reliance on delivery by trained mental health professionals in clinic or community settings. Although implementation studies of BPT have been reported these results lack generalizability because of their methodological idiosyncrasies in implementation. To maximize the public health benefits of BPT systematic implementation studies are needed particularly in underserved community settings. In Appalachia a region recognized for its dramatic health disparities at least one in five children exhibits sub-clinical to clinical levels of disruptive behavior problems. Risk factor for child disruptive behavior problems are pervasive; Appalachian residents suffer high poverty rates low education levels disproportionately high rates of substance abuse and mental health disorders and persistent disparities in a wide range of health problems. A challenging combination of cultural barriers and poor access to mental health services hinders the usual delivery model for BPT in Appalachia (i.e. by trained mental health professionals). The vast majority of Appalachian counties are designated as mental health provider shortage areas and cultural considerations (e.g. distrust of outsiders the primacy of kinship networks history of authoritarian parenting styles strong self-reliance) may limit uptake of the few services available. The goal of this mixed-methods pilot study is to prepare for a future large-scale hybrideffectiveness-implementation trial of an evidence-based BPT intervention across rural Appalachian communities. Our preliminary data revealed community preferences for brief BPT delivery by local community health workers. Thus to increase the accessibility and acceptability of BPT in this region we will use the ADAPT-ITT framework to systematically adapt the delivery model for the Family Check-Up a brief BPT intervention previously shown to be effective in reducing behavior problems and preventing negative outcomes when delivered by trained mental health professionals in clinic and community settings. Following the systematic adaptation of the Family Check-Up delivery model we will pilot-test its implementation by community health workers in four high-need under- resourced Appalachian communities to assess feasibility acceptability and costs. Our primary questions are whether we can effectively train community health workers in these communities to deliver the Family Check- Up with fidelity; whether we can enroll parents/caregivers and children to initiate and complete the intervention; and whether the battery of assessments and measures planned for the subsequent R01 effectiveness- implementation trial are feasible and appropriate for these community settings.

project_terms:
Address;Aggressive behavior;Appalachian Region;Area;Authoritarianism;Behavioral;Behavioral Model;Behavioral trial;Caregivers;Caring;Child;Child Behavior;Child Mental Health;Child Rearing;Church;Clinic;Clinical;Communities;Community Health Aides;County;Data;Development;Disruptive Behavior Disorder;Educational Background;Educational Intervention;Effectiveness;Enrollment;Ensure;Evidence based intervention;Exhibits;Failure;Family;Feedback;Foundations;Future;Gap Junctions;Goals;Health;Health Benefit;Health Personnel;Health Professional;Health Services Accessibility;Health Services Research;Healthcare;Home environment;Hybrids;Individual;Intervention;Kinship Networks;Lead;Location;Longevity;Measures;Mental Health;Mental Health Services;Mental disorders;Methodology;Methods;Modality;Modeling;National Institute of Mental Health;Nursery Schools;Outcome;Parents;Pilot Projects;Poverty;Prevalence;Problem behavior;Protocols documentation;Public Health;Recording of previous events;Reporting;Research Project Grants;Research Support;Resistance;Resources;Risk;Risk Factors;Rural;Schools;Services;Societies;Standardization;Substance abuse problem;Symptoms;Testing;Training;Training Programs;Underserved Population;Work;aged;antisocial behavior;behavioral study;checkup examination;community setting;cost;early childhood;evidence base;experience;health disparity;implementation research;implementation science;implementation trial;innovation;medical specialties;mental training;preference;prevent;public health relevance;self reliance;social stigma;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Early childhood disruptive behavior problems lead to significant costs to families and society but can be reduced with behavioral parent training interventions. To increase the public health impact of these interventions their feasibility accessibility and acceptability in high-need underserved communities must be ensured. This pilot project will systematically adapt and pilot-test the delivery model of an existing effective parent training intervention for implementation in rural Appalachia a region with many documented health disparities high levels of poverty and shortages of mental health providers.


application_id: 9220821
project_number: 5R34DA038869-03
project_title: A Feasibility Trial for Inhibitory-Control Training to Reduce Cocaine Use
administering_ic: NIDA
award_notice_date: 2017-01-25
opportunity_number: PA-13-078
application_type: 5
activity_code: R34
ic: DA
serial_number: 038869
program_official: AKLIN, WILL
project_start_date: 2015-03-15
project_end_date: 2018-01-31
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine abuse is an unrelenting public-health concern. Behavioral therapies are considered the "standard of care" for reducing cocaine use and preventing relapse. However even with intense behavioral interventions rates of relapse to cocaine use are discouragingly high (i.e. 60-95% of patients return to drug use). Novel strategies are urgently needed to improve treatment outcomes for cocaine-use disorders. The overarching goal of this project is to assess the feasibility acceptability and initial efficacy o an innovative cocaine-based inhibitory-control training procedure. This goal will be accomplished through the conduct of a Stage I pilot trial. Cocaine-dependent participants will be enrolled and randomized to receive inhibitory-control training to cocaine or neutral images (N=20/condition). This proposed intervention cocaine- based inhibitory-control training will be delivered using an innovative computer program which teaches cocaine abusers to inhibit a pre-potent response to cocaine or neutral cues. The primary hypothesis is the proposed procedures are feasible and acceptable to the participants. Feasibility will be assessed by determining time needed to enroll the target sample; adaptive randomization outcomes; maintenance of blind for blinded study personnel; participant attendance completion and adherence to study procedures. Acceptability will be determined using a Treatment Acceptability Questionnaire. The secondary hypothesis is that participants receiving cocaine-based inhibitory-control training will reduce their drug use toa greater extent than their counterparts in the neutral-image condition. Reduced cocaine use will be demonstrated by fewer positive-urine samples using qualitative urinalysis and a reduction in levels of benzoylecgonine as determined by quantitative urinalysis (i.e. ELISA). The third hypothesis is that participants receiving cocaine-based inhibitory-control training will show improved inhibitory control and neurocognitive functioning relative to their counterparts in the neutral-image condition. Improved inhibitory control impulsivity and cognitive functioning will bedemonstrated using a battery of clinical instruments and laboratory tasks. The proposed research is highly innovative in that it will provide critical information regarding the feasibilit acceptability initial efficacy of cocaine-based inhibitory-control training to reduce drug use andimprove inhibitory control and neurocognitive functioning in cocaine-dependent participants. Cocaine-based inhibitory- control training is also easy to administer (i.e. 15 minutes) inexpensive need not be administered by a clinician and could easily be incorporated into current behavioral or community-based treatment approaches to enhance sustained abstinence thereby quickly impacting clinical research and practice. The cocaine-based inhibitory-control training program could also be converted to a smart-phone for administration outside the clinic. Administering training outside of the clinic would allow patients to receive more frequent booster sessions further improving sustained abstinence by allowing them to be exposed to therapy as needed.

project_terms:
Abstinence;Address;Adherence;Alcoholic beverage heavy drinker;Alcohols;Behavior Therapy;Behavioral;Blinded;Cellular Phone;Clinic;Clinical;Clinical Research;Cocaine;Cocaine Abuse;Cocaine Dependences;Cues;Development;Disease;Double-Blind Method;Drug usage;Ecology;Educational process of instructing;Employee Strikes;Enrollment;Enzyme-Linked Immunosorbent Assay;Future;Gambling;Goals;Human Resources;Image;Impulsivity;Intervention;Intervention Studies;Iowa;Laboratories;Maintenance;Modification;NIH Program Announcements;Neurocognitive;Outcome;Participant;Patients;Procedures;Program Development;Public Health;Questionnaires;Randomized;Relapse;Research;Risk;Sampling;Signal Transduction;Testing;Time;Training;Training Programs;Treatment outcome;Urinalysis;Urine;attentional bias;base;benzoylecgonine;blind;clinical practice;cocaine use;cognitive function;community based treatment;computer program;discount;discounting;drinking;efficacy trial;improved;improved outcome;innovation;instrument;novel strategies;pilot trial;prevent;prospective;public health relevance;response;standard of care;therapy development;trial design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The research proposed in this application will demonstrate the feasibility acceptability and initial efficacy of an innovative cocaine-based inhibitory-contol training procedure for cocaine-use disorders. A Stage I double blind pilot trial will be conducted. The proposed research is innovative because cocaine-based inhibitory- control training is easy to administer (i.e. requires about 15 minutes) inexpensive need not be administered by a clinician and could easily be incorporated into current behavioral or community-based treatment approaches to enhance sustained abstinence.


application_id: 9220718
project_number: 5R21AI120602-02
project_title: Bpur a critical regulator of Borrelia burgdorferi infectivity
administering_ic: NIAID
award_notice_date: 2017-01-19
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 120602
program_official: ILIAS, MALIHA R
project_start_date: 2016-02-10
project_end_date: 2019-01-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)S]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): All organisms from bacteria to humans need to "recognize" where they are and respond accordingly. A pathogen must sense its location in the infectious cycle then produce factors necessary for that site while repressing synthesis of inappropriate factors. Thus disruption of key regulatory pathways can inhibit a pathogen's ability to infect indicating useful targets for developing novel antibiotics. In our studies of th Lyme disease bacterium Borrelia burgdorferi we discovered that regulation of a new DNA/RNA-binding protein named BpuR is required for mammalian infection. B. burgdorferi regulates production of BpuR synthesizing it at low levels during mammalian infection processes and at high levels during colonization of vector ticks. We genetically engineered B. burgdorferi to constitutively produce high levels of BpuR during murine infection and found the mutant to be significantly impaired in its ability to colonize mice. Transcriptomic analyses (RNA-Seq) demonstrated that BpuR significantly affects expression of approximately 5% of B. burgdorferi operons disturbing cellular levels of several known virulence factors and metabolic enzymes. We hypothesize that disruption of the processes controlling production of BpuR will significantly inhibit B. burgdorferi infection. The planned studies are designed to elucidate the mechanism by which B. burgdorferi controls expression of this critical regulatory factor and determine how disrupting that mechanism impacts upon infection processes.

project_terms:
Affect;Antibiotics;Arthropods;Bacteria;Bacterial Infections;Binding;Borrelia;Borrelia burgdorferi;DNA;DNA Sequence;Data;Engineering;Enzymes;Genes;Genetic Engineering;Genetic Transcription;Glycine;Human;Impairment;Infection;Link;Location;Lyme Disease;Mammals;Metabolic;Modeling;Mus;Mutate;Names;North America;Operon;Organism;Patients;Process;Production;Protein Biosynthesis;Proteins;RNA Sequences;RNA-Binding Proteins;Regulation;Regulatory Pathway;Site;Testing;Ticks;Transcriptional Regulation;Transfer RNA;Virulence Factors;design;human disease;mutant;novel;novel therapeutics;pathogen;public health relevance;transcriptome sequencing;transcriptomics;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The BpuR protein of the Lyme disease bacterium binds specific sequences of DNA and RNA and controls expression of numerous virulence factors and essential metabolic enzymes. Bacteria that do not correctly control BpuR levels are severely impaired in ability to cause mammalian infection. Studies in this proposal will determine the mechanisms by which Lyme bacteria control BpuR production and define how disruption of those mechanisms impacts upon infection processes.


application_id: 9219942
project_number: 1R01DK112034-01
project_title: Mechanisms regulating neurotensin secretion and function
administering_ic: NIDDK
award_notice_date: 2017-01-19
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DK
serial_number: 112034
program_official: SERRANO, JOSE
project_start_date: 2017-02-01
project_end_date: 2022-01-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
5'-AMP-activated protein kinase;Adipose tissue;Affinity;Amino Acids;Assimilations;Attenuated;Biochemistry;Biometry;Body mass index;Cells;Clinical;Colorectal Cancer;Complex;Computational Biology;Consumption;Development;Diabetes Mellitus;Diet therapy;Dietary Fats;Digestion;Distant;Drosophila genus;Endocrinology;Enterocytes;Enteroendocrine Cell;Epidemiology;Epigenetic Process;FRAP1 gene;Fasting;Fat Body;Fatty Liver;Fatty acid glycerol esters;Food;Future;Gastrointestinal Physiology;Genes;Genetic;Goals;Growth;Hepatocyte;High Fat Diet;Homeostasis;Hormones;Human;Ingestion;Innovative Therapy;Insulin Resistance;Intestinal Absorption;Intestinal Mucosa;Intestines;Knockout Mice;Laboratories;Lead;Length;Link;Lipids;Liver;MAPK3 gene;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mediating;Metabolic Diseases;Metabolism;Midgut;Molecular;Morbidity - disease rate;Mus;Neurotensin;Neurotensin Receptors;Nonesterified Fatty Acids;Nutrient;Obesity;Overnutrition;Peptides;Physiology;Play;Population Study;Process;Protein Kinase;Regulation;Risk;Role;Signal Pathway;Signal Transduction;Site;Small Intestines;Stimulus;Stomach;System;Time;Transgenic Organisms;Woman;absorption;base;blood glucose regulation;cardiovascular disorder risk;cell motility;disorder risk;epidemiology study;lipid metabolism;mTOR inhibition;malignant breast neoplasm;mortality;mouse model;multidisciplinary;non-alcoholic fatty liver;novel;overexpression;receptor;response;sortilin;uptake


application_id: 9218609
project_number: 1R01EY027407-01
project_title: Disinhibition and experience-dependent visual plasticity
administering_ic: NEI
award_notice_date: 2017-05-04
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: EY
serial_number: 027407
program_official: GREENWELL, THOMAS
project_start_date: 2017-06-01
project_end_date: 2021-05-31
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 10356866
contact_pi: MCGEE, AARON W
other_pis: TRACHTENBERG, JOSHUA ;XU, XIANGMIN
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adolescent;Adult;Amblyopia;Behavioral;Brain;Calcium;Child;Childhood;Childhood Neurological Disorder;Chronic;Development;Disinhibition;Electrophysiology (science);Exhibits;Eye;Genes;Image;In Vitro;Interneurons;Knock-out;Knowledge;Lasers;Lazy Eyes;Life;Maps;Measures;Mediating;Modeling;Modification;Mus;Mutant Strains Mice;Nervous system structure;Neurodevelopmental Disorder;Neurons;Ocular Dominance;Parvalbumins;Pattern;Phenotype;Population;Receptor Gene;Recovery;Research;Resolution;Scanning;Strabismus;Synapses;Testing;Therapeutic;Vision;Vision Disorders;Visual;Visual Acuity;Visual Cortex;Visual system structure;Wild Type Mouse;brain circuitry;cortex mapping;critical period;developmental plasticity;effective therapy;excitatory neuron;experience;experimental study;flexibility;hippocampal pyramidal neuron;improved;in vivo;in vivo calcium imaging;monocular deprivation;mouse model;mutant;neural circuit;neuronal patterning;presynaptic;programs;response;restoration;visual plasticity;visual processing;young adult


application_id: 9215637
project_number: 5R21AI124649-02
project_title: Mutagenesis in Chlamydia trachomatis via allelic exchange
administering_ic: NIAID
award_notice_date: 2017-01-25
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 124649
program_official: VINCENT, LEAH REBECCA
project_start_date: 2016-02-08
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZRG1-IDM-V(02)M]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlamydia trachomatis represents a significant health concern in the United States. A substantial burden exists due to the prevalence and the combined health and socioeconomic impact of acute and chronic disease. Chlamydiae are obligate intracellular parasites that undergo a complex developmental cycle. All Chlamydia species express a type III secretion system (T3SS) and based on analogy with other T3SS-expressing pathogens this mechanism likely contributes significantly to overall pathogenesis. Although definitive association of T3S with chlamydial virulence has proven difficult the newly-acquired ability to genetically manipulate chlamydiae has opened new doors for progress. We present preliminary data describing the first ever Chlamydia-specific suicide vector and propose to leverage this new approach to target T3SS genes for inactivation. Specifically we will further develop the suicide vector system and directly create null mutations in specific T3S effector genes. We also propose approaches to conditionally inactivate T3S capability. At the end of these studies we will have established molecular tools that will benefit the entire Chlamydia research community. In addition we will gain a better understanding of how the T3SS contributes to chlamydial virulence.

project_terms:
Acute Disease;Alleles;Biology;Cells;Chemicals;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chronic Disease;Communities;Complement;Complex;Data;Development;Dissection;Dominant-Negative Mutation;Ectopic Expression;Epithelial Cells;Essential Genes;Gene Deletion;Gene Silencing;Gene Targeting;Generations;Genes;Genetic;Genome;Goals;Growth;Health;Human;Infection;Insertional Mutagenesis;Investigation;Learning;Methods;Microbiology;Molecular;Mutagenesis;Pathogenesis;Pharmacology;Prevalence;Protein Secretion;Proteins;RNA Interference;Research;Role;Sexually Transmitted Diseases;Suicide;System;Techniques;Type III Secretion System Pathway;United States;Virulence;Work;base;chemical genetics;gene product;genetic approach;genetic manipulation;inducible gene expression;inhibitor/antagonist;link protein;loss of function;member;mutant;new technology;novel;novel strategies;null mutation;obligate intracellular parasite;pathogen;protein function;protein protein interaction;public health relevance;socioeconomics;success;suicide vector;tool;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Sexually transmitted disease remains a significant health burden world-wide and infections with Chlamydia trachomatis are common. We have developed a novel method to generate null mutations in chlamydial genes and will leverage this approach to gauge the importance of selected type III secretion proteins in chlamydial pathogenesis.


application_id: 9213910
project_number: 1R01HL134731-01
project_title: Serum Amyloid A Inflammasome Activation and Abdominal Aortic Aneurysms
administering_ic: NHLBI
award_notice_date: 2016-12-16
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 134731
program_official: MCDONALD, CHERYL
project_start_date: 2017-01-01
project_end_date: 2020-12-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: DE BEER, FREDERICK C.
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abdominal Aortic Aneurysm;Acute;Age-Years;Angiotensin II;Antisense Oligonucleotides;Aortic Rupture;Apolipoprotein E;Attenuated;Biological;Biological Markers;Blood Vessels;CASP1 gene;CCL2 gene;Caring;Cell Culture Techniques;Cells;Cessation of life;Chronic;Clinical Management;Data;Deposition;Development;Elastin;Evaluation;Event;Generations;High Density Lipoproteins;Human;Infection;Infiltration;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory Response;Infusion procedures;Injury;Interleukin-1 beta;Intervention;Laboratories;Liver;Matrix Metalloproteinases;Medial;Mediating;Mus;Operative Surgical Procedures;Pathologic;Patients;Plasma;Proteins;Publications;Publishing;Reactive Oxygen Species;Risk;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Serum amyloid A protein;Signal Transduction;Smooth Muscle Myocytes;Staining method;Stains;Symptoms;TNF gene;Testing;Tissues;Transgenes;United States;Viral Vector;Woman;adeno-associated viral vector;base;effective therapy;human old age (65+);indexing;innovation;insight;macrophage;men;mouse model;novel;novel strategies;predictive marker;prospective;response;small molecule;therapeutic target;translational study;unpublished works;vascular inflammation


application_id: 9213310
project_number: 5R01DE022597-05
project_title: Bacterial peptidylarginine deiminase a link between gums and joint disease
administering_ic: NIDCR
award_notice_date: 2017-01-26
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DE
serial_number: 022597
program_official: CHANDER, PREETHI
project_start_date: 2013-02-01
project_end_date: 2019-01-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Porphyromonas gingivalis is a leading pathogen in chronic periodontitis a disease process involving progressive destruction of tissues that support the teeth. Recently the organism has been reported to produce a unique bacterial enzyme P. gingivalis peptidylarginine deiminase (PPAD) which has the ability to convert arginine residues in proteins to citrulline. Protein citrullination alters protein structure and function hence PPA may be involved in dysregulation of the host's signaling network for immune evasion. Further accumulating evidence has revealed the role of autoimmunity against citrullinated proteins in the development of rheumatoid arthritis (RA). As inflammatory conditions in the lungs of cigarette smokers contributes to the breakdown of immune tolerance to citrullinated epitopes chronic exposure to citrullinated proteins at periodontitis sites may also predispose susceptible individuals to the development of autoantibodies and initiation of RA. Thus PPAD may represent the mechanistic link between periodontitis and rheumatoid arthritis - diseases that are known to be significantly associated to each other at the epidemiological level.  We hypothesize that citrullination of bacterial and host proteins in periodontal/gingival tissues by PPAD within the chronic inflammatory environment and immune system stimulation by bacteria- derived "danger signals" leads to the initial break of immune tolerance to citrullinated proteins and peptides. In addition PPAD may manipulate immune responses in inflamed periodontal tissues by modifying important effector molecules of the innate immunity including C3a and C5a anaphylatoxins and bradykinin. Biological activity of these peptides depends on the C-terminal arginine which is also a preferential target for PPAD. Hence this research proposal will investigate the important and innovative concept that PPAD as a virulence factor of P. gingivalis and mechanistic link between periodontitis and RA with the following specific aims: (i) in vivo and ex vivo examination of PPAD's role in the pathogenesis of RA; (ii) functional and structural studies of various forms of PPAD; and (iii) investigate the immunomodulatory effect of PPAD that is relevant to the pathogenesis of periodontal disease. Thus the proposed research will illuminate the PPAD's contribution to chronic inflammation driven by P. gingivalis infection and shed light on the possible link between periodontal disease and rheumatoid arthritis. This knowledge will create new perspectives in the treatment of periodontitis and prevention of rheumatoid arthritis in susceptible individuals.

project_terms:
Affect;Anaphylatoxins;Antibodies;Arginine;Atherosclerosis;Autoantibodies;Autoimmune Responses;Autoimmunity;Bacteria;Bioinformatics;Biological;Bone Resorption;Bradykinin;C-terminal;Caspase;Chronic;Cigarette Smoker;Citrulline;Clinical;Collagen-Induced Arthritis;Complement;Complement 3a;Complement 5a;Complement Activation;Complex;Connective Tissue;Data;Dental Plaque;Development;Disease;Enzymes;Epidemiology;Epitopes;Exposure to;Forsythia;Generations;Gingiva;Gingival Crevicular Fluid;Glycine decarboxylase;Homeostasis;Homologous Gene;Human;Immune;Immune Evasion;Immune Tolerance;Immune response;Immune system;Individual;Infection;Inflammation;Inflammatory;Innate Immune Response;Intervention;Joints;Kinins;Knowledge;Lesion;Light;Link;Lung;Molecular;Natural Immunity;Organism;Pathogenesis;Pathogenicity;Pathologic;Pathology;Patients;Peptides;Peptidoglycan;Periodontal Diseases;Periodontitis;Physiological;Population;Porphyromonas gingivalis;Post-Translational Protein Processing;Predisposition;Prevention;Process;Protein-arginine deiminase;Proteins;Reaction;Reporting;Research;Research Proposals;Resistance;Rheumatoid Arthritis;Role;Sequence Analysis;Signal Transduction;Site;Source;Substrate Specificity;Synovial Fluid;System;TNFRSF10A gene;Tissues;Tooth Loss;Tooth structure;Transgenic Mice;Treponema denticola;Validation;Virulence Factors;alveolar bone;arthropathies;bactericide;base;citrullinated protein;complement pathway;gingipain;immunoregulation;in vivo;inflammatory milieu;innovation;interest;microbial;microbial genome;novel strategies;pathogen;pathogenic bacteria;polypeptide;preference;protein function;protein structure;public health relevance;three dimensional structure;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis is characterized by the development of autoantibodies against citrullinated proteins within the joints in susceptible individuals. Porphyromonas gingivalis a known periodontal pathogen is the only known bacterium which produces an enzyme (PPAD) that is capable of converting arginine residues in proteins into citrullin. It is hypothesized that PPAD activity in inflamed infected periodontal tissues not onlycontributes to the pathology of periodontitis but also may promote breakdown of immunotolerance and initiates the development of rheumatoid arthritis.


application_id: 9212895
project_number: 7R03DC014319-03
project_title: Integration of taste and olfactory signals in gustatory cortex
administering_ic: NIDCD
award_notice_date: 2016-03-18
opportunity_number: PAR-13-057
application_type: 7
activity_code: R03
ic: DC
serial_number: 014319
program_official: SULLIVAN, SUSAN L
project_start_date: 2014-12-01
project_end_date: 2017-11-30
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 8305266
contact_pi: SAMUELSEN, CHAD L
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Integration of sensory information from multiple modalities is believed to enhance the detection of convergent stimuli. This multimodal integration was originally theorized to occur only in higher order cortical areas such as prefrontal cortex. However recent research has shown multimodal sensory responses in every primary sensory cortex including gustatory cortex (GC). GC is the primary cortex responsible for processing information related to taste and is known to code multisensory information related to taste such as temperature touch and anticipatory cues. However the most conspicuous sensory interaction that of taste and olfaction has not been explored at the GC circuit-level. Taste and olfaction are intimately linked. Anatomical and neuroimaging studies have begun to describe the synergistic integration of these two modalities and suggest GC as a primary integrative chemosensory node. Despite this great progress very little information is available on whether and how single neurons in GC integrate multimodal chemosensory integration. The proposed research is a three step approach all of which rely upon multielectrode techniques to record ensembles of single neurons in GC while rats intraorally sample tastes and odors. The first experiment is designed to determine how taste and odor are represented by single neurons in GC. After a better understanding of GC chemosensory response the second experiment will test the hypothesis that odor-taste experience modulates chemosensory activity in GC. The third experiment continues along this trajectory to explore how incongruent odor-taste mixtures suppress chemosensory activity in GC. Altogether the experiments outlined in this R03 proposal will lay a foundation for an in depth understanding of the circuit-level integration of multimodal chemosensory information in GC of alert rodents. If successful this research will elucidate how single neurons in GC process ecologically synergistic chemosensory information and will establish GC as a primary area of multisensory integration of stimuli related to food.

project_terms:
Acetates;Address;Altered Taste;Animal Model;Animals;Area;Association Learning;Behavioral;Benzaldehyde;Beverages;Cannulas;Citric Acid;Code;Consummatory Behavior;Cues;Data;Detection;Diet;Eating Disorders;Electrodes;Electrophysiology (science);Epithelial;Food;Foundations;Goals;Health;Home environment;Implant;Individual;Knowledge;Lead;Learning;Link;Modality;Nasal Epithelium;Nasal cavity;Neurons;Nose;Odors;Olfactory Pathways;Oral;Prefrontal Cortex;Process;Property;Quinine;Rattus;Research;Rodent;Role;Sampling;Sensory;Shapes;Signal Transduction;Site;Smell Perception;Stimulus;Sucrose;Taste Perception;Techniques;Temperature;Testing;Tongue;Touch sensation;Training;Water;design;drinking;experience;food consumption;information processing;multisensory;neuroimaging;olfactory receptor;preference;receptor;research study;response;sensory cortex;sensory integration;taste system

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposal aims to understand how neurons in the gustatory cortex (GC) integrate the chemosensory modalities of taste and smell. In rodents GC has been traditionally studied for its involvement in taste. Recent data suggests that neurons in GC are multimodal processing taste-related information such as temperature touch and anticipatory cues. While the role of GC in processing taste information is well established very little is known about its involvement in integrating olfactory information. With this proposal we intend to study how neurons in GC integrate and encode naturally related chemosensory information taste and odor. Multielectrode recordings in behaving rats will unveil how GC neurons represent tastes and retronasal odors how experience of an odor- taste association alters that representation and finally how odor-taste association learning modulates chemosensory activity. The results of these efforts will lay the foundation for an in depth understanding of ecologically related multimodal chemosensory processing at the circuit level in GC. If successful this research will expand our knowledge of chemosensory processing point to GC as a primary integrative area of information related to consummatory behaviors and reveal an area to study the interactions between chemosensory processing and behavioral food choice in animal models of eating disorders.


application_id: 9212794
project_number: 5K01DA031961-04
project_title: Glutamate Receptor Modulation of Calcium Signaling in Neuropathic Pain
administering_ic: NIDA
award_notice_date: 2017-01-10
opportunity_number: PA-11-190
application_type: 5
activity_code: K01
ic: DA
serial_number: 031961
program_official: RAPAKA, RAO
project_start_date: 2014-02-01
project_end_date: 2019-01-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 10670168
contact_pi: DOOLEN, SUZANNE
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long term goal of this K01 career award is to understand the mechanisms that lead to injury-induced central sensitization and to establish ameliorative therapeutic targets for chronic pain. My preliminary data suggests that AMPA receptors drive glutamate-evoked Ca2+ transients in spinal cord neurons and that glutamate-evoked Ca2+ transients are potentiated following nerve injury. The central hypothesis is that nerve injury potentiates neuronal activity and Ca2+ mobilization (Aim 1) via increased GluR2 AMPA receptor phosphorylation and trafficking in the dorsal horn (Aim 2) and that this mechanism of neuropathic pain is tonically inhibited by endogenous opioids (Aim 3). This hypothesis will be tested using innovative simultaneous Ca2+ imaging and whole-cell electrophysiology to evaluate dorsal root stimulated (DRS) Ca2+ transients and neuronal activity in dorsal horn of adult spinal cord slices. Aim 1. Experiment 1a will evaluate the effect f sham or spared nerve injury (SNI) on isolated AMPA receptor Ca2+ signals and membrane currents. Experiment 1b will evaluate Ca2+ mobilization and membrane currents DRS at A A and c-fiber activation strength. Aim 2 While AMPA GluR2 phosphorylation and trafficking have been implicated in inflammatory pain the mechanisms that mediate nerve injury-induced potentiation of Ca2+ levels are not known. To address this question Experiment 2a will determine levels and subcellular localization of total and phosphorylated GluR2 in dorsal horn. Based on studies indicating inflammation-induced GluR2 internalization is NMDA receptor-dependent Experiment 2b will test the hypothesis that intrathecal administration of NMDA receptor antagonists will reduce nerve-injury induced phosphorylation and internalization of GluR2. Aim 3. My new data suggest that opioids tonically inhibit glutamate receptor function after inflammation and thus mask neuropathic pain. Aim 3 seeks to extend this discovery to our model of peripheral neuropathic pain. Experiment 3a will attempt to correlate Ca2+ mobilization with pain-like behavior following traditional SNI and a modified nerve injury model that resolves over 4 weeks. Establishing a decrease in Ca2+ mobilization in association with behavioral resolution will allow us to test our hypothesis in Experiment 3b. Experiment 3b will evaluate the effects of opioid receptor antagonists on: DRS-stimulated Ca2+ transients and neuronal activity and GluR2 phosphorylation and subcellular localization. We expect that opioid receptor antagonists will increase Ca2+ mobilization neuronal activity GluR2 phosphorylation and shift Ca2+-impermeable GluR2 expression away from the cell surface.

project_terms:
AMPA Receptors;Address;Adult;Adverse effects;Analgesics;Award;Behavior;Behavioral;C Fiber;CTOP;Calcium;Calcium Signaling;Cell Fractionation;Cell surface;Cells;Chemosensitization;Data;Electrophysiology (science);Endogenous Opiates;Glutamate Receptor;Glutamates;Goals;Healthcare;Hyperalgesia;Image;Inflammation;Inflammatory;Injury;Lead;Masks;Mediating;Membrane;Mentors;Mission;Modeling;Mus;N-Methyl-D-Aspartate Receptors;NMDA receptor antagonist;Naltrexone;National Institute of Drug Abuse;Neurons;Opioid;Opioid Receptor;Pain;Pain management;Peripheral;Permeability;Phosphorylation;Receptor Activation;Receptor Signaling;Research;Research Technics;Resolution;Signal Transduction;Slice;Spinal Cord;Techniques;Testing;Western Blotting;base;career;central sensitization;chronic pain;clinically relevant;dorsal horn;experimental study;inflammatory pain;innovation;mu opioid receptors;nerve injury;neuronal excitability;painful neuropathy;postsynaptic;public health relevance;receptor function;response;sensory input;spared nerve;spinal nerve posterior root;therapeutic target;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. This project is relevant to NIDA's mission because it will 1) determine mechanisms that lead to injury-induced central sensitization and 2) establish clinically relevant therapeutic targets for alleviating chronic pain and 3) target mechanisms of endogenous opioids on long-lasting pain vulnerability following injury. This Research Plan employs highly innovative wide-field calcium imaging from numerous cells in a single spinal cord slice from adult mice.


application_id: 9212761
project_number: 5R01AA021978-04
project_title: Role of ECM and inflammatory remodeling in alcohol-induced liver and lung damage
administering_ic: NIAAA
award_notice_date: 2017-01-12
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AA
serial_number: 021978
program_official: RADAEVA, SVETLANA
project_start_date: 2014-02-01
project_end_date: 2019-01-31
study_section: Special Emphasis Panel[ZRG1-DKUS-D(03)M]
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overarching theme of this project is to study the role of nutrition and gut flora/intestinal dysfunction on alcohol-induced organ injury. We will focus on two organs that are the most common victims of chronic alcohol abuse: liver and lung. Specifically we will examine how alcohol activates tissue remodeling in liver and lung through the induction of plasminogen activator inhibitor-1 (PAI-1) and the consequences of these events. Novel in vitro and in vivo approaches will be used to address mechanisms of action with the goal of identifying new targets for intervention. We propose that liver and lung share similar mechanisms of organ damage in response to alcohol. We specifically propose that PAI-1 induction and subsequent extracellular matrix (ECM) remodeling are key to the early inflammatory changes in both organs. Considering observations linking the effects of alcohol on tissue remodeling in both organs we further propose that liver and lung not only share mechanisms of injury in response to alcohol but that these mechanisms are linked and represent interdependent events. Based on these observations and other preliminary data this proposal will test the hypothesis that alcohol through the activation of nicotinic acetylcholine receptors (nAChRs) induces the expression of PAI-1 in both liver (e.g. Kupffer cells) and lung (Type II epithelial cells). This in turn triggers a series of downstream events that promote live and lung injury in response to endotoxemia derived from the GI tract. Moreover we propose that liver-derived mediators further exacerbate lung injury through the induction of inflammation and tissue remodeling enhanced by inhibition of fibrinolysis. These hypotheses will be tested in the following Specific Aims: Aim 1: To explore the role of PAI-1 and nAChRs in the susceptibility of liver and lung to acute injury observed in the setting of chronic alcohol exposure. We hypothesize that alcohol stimulates the expression of PAI-1 in both liver and lung cells through effects on specific nAChRs. This in turn sensitizes both organs to acute injury (e.g. LPS). Aim 2: To test the hypothesis that liver-derived mediators are involved in pulmonary changes caused by chronic alcohol exposure and LPS- related organ damage. We propose that alcohol-induced damage to the liver sensitizes the host to acute lung injury in at-risk individuals. To test this e plan to evaluate the effects of alcohol on lung injury in animals with reduced hepatotoxicity usinggenetically engineered and chimeric mice. Aim 3: To determine the role of gut- derived products on alcohol-induced lung damage. Gut changes/injury caused by alcohol consumption could directly or indirectly damage liver and lung tissue. However how gut:lung or gut:liver:lung interactions are influenced by alcohol remains unknown. We propose to test these concepts and to explore the effect of novel therapeutic interventions that target the GI tract to protect th lung.

project_terms:
Acute;Acute Lung Injury;Address;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcoholic Liver Diseases;Alcohols;Animals;Cells;Chronic;Clinical;Comorbidity;Data;Deposition;Disease;Endotoxemia;Epithelial Cells;Ethanol;Event;Extracellular Matrix;Fibrin;Fibrinolysis;Functional disorder;Gastrointestinal tract structure;Genetic Engineering;Goals;Health;Hepatic;Hepatotoxicity;Hypoxemia;In Situ;In Vitro;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Intestines;Investigation;Kupffer Cells;Laboratories;Lead;Link;Liver;Lung;Lung Inflammation;Mediating;Mediator of activation protein;Modeling;Morbidity - disease rate;Mus;Nicotinic Receptors;Organ;Peptide Hydrolases;Plasminogen Activator Inhibitor 1;Predisposition;Preparation;Pulmonary Edema;Risk;Role;Series;Structure of parenchyma of lung;Testing;Tissues;Translating;Up-Regulation;Work;alcohol effect;alcohol exposure;alcohol response;base;in vivo;liver inflammation;liver injury;lung injury;mortality;new therapeutic target;novel;novel therapeutic intervention;nutrition;problem drinker;public health relevance;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alcohol-induced organ damage is a major health concern. The liver and lungs are major target organs of alcohol damage but the mechanisms of injury remain unclear and there are no therapies for these diseases. This project test the overall hypothesis that liver and lung inflammation caused by ethanol is mediated by fibrin ECM deposition. Taken together these studies will establish new models of alcoholic injury explore multiple overlapping mechanisms and provide novel targets for therapies.


application_id: 9212698
project_number: 5P40OD019794-03
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2017-02-24
opportunity_number: PAR-14-005
application_type: 5
activity_code: P40
ic: OD
serial_number: 019794
program_official: CONTRERAS, MIGUEL A
project_start_date: 2015-03-01
project_end_date: 2020-02-29
study_section: Special Emphasis Panel[ZRG1-BBBP-Y(45)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application seeks support to continue operations of the Ambystoma Genetic Stock Center (AGSC) at the University of Kentucky. The AGSC maintains a historically significant collection of Mexican axolotls (Ambystoma mexicanum) an endangered species that provides living materials in support of biomedical research nationally and internationally. Most notably axolotls are studied because they are unique among vertebrates in being able to regenerate numerous tissues and body parts. These include the spinal cord limbs jaw retina brain heart and tail all of which can be regenerated at any poit during embryonic larval and adult life. Also axolotls are used by researchers that work in many additional areas including neurobiology ecotoxicology development physiology cell biology genetics genomics and evolution. Over the next 5 years the AGSC will implement a new resource management plan to better ensure long-term sustainability of axolotl stocks and move each year towards greater self- sufficiency. This will be accomplished by providing high quality stocks that the community has come to depend upon increasing production and distribution of axolotls and offering new products and services. In particular the AGSC will offer a microinjection service to assist investigators in the creation of transgenic axolotls. The AGSC will continue to serve as an informatics hub where investigators obtain information about the collection technical procedures potential collaborators and research findings. Overall the project will ensure distribution and long-term sustainability of axolotl resources to NIH-funded investigators.

project_terms:
Adolescent;Adult;Advisory Committees;Ambystoma;Ambystoma mexicanum;Applied Research;Area;Behavior;Biological;Biomedical Research;Body part;Brain;Breeding;Cells;Cellular biology;Collection;Communities;Community Services;Computers;Custom;Data;Development;Embryo;Embryonic Development;Ensure;Equipment;Evolution;Funding;Genes;Genetic;Genome;Genomics;Health;Heart;Hour;Human;IACUC;Informatics;Injectable;Injection of therapeutic agent;Institution;International;Jaw;Kentucky;Knock-in;Life;Limb structure;Methods;Microinjections;Mission;Modeling;Monitor;Natural regeneration;Neurobiology;Organ Model;Organism;Physiology;Population;Preparation;Procedures;Production;Protocols documentation;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Retina;Services;Site;Site-Directed Mutagenesis;Speed;Spinal Cord;System;Tail;Time;Tissues;Transgenic Organisms;Translating;United States National Institutes of Health;Universities;Vertebrates;Visit;Work;animal resource;base;experience;gene function;innovation;knowledge base;learning strategy;meetings;operation;organ regeneration;public health relevance;tissue repair;transcription activator-like effector nucleases;web site

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Living stock resources are needed for the Mexican axolotl so that biomedical investigators can translate biological information to humans. The Mexican axolotl is a primary vertebrate model for organ regeneration tissue repair and post--- embryonic development.


application_id: 9212643
project_number: 5R01HD064993-08
project_title: Aging and Dementia in Down Syndrome: Connectivity Inflammation and Cerebrovascular Contributions
administering_ic: NICHD
award_notice_date: 2017-01-25
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 064993
program_official: PARISI, MELISSA
project_start_date: 2009-09-30
project_end_date: 2020-01-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: SCHMITT, FREDERICK
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of AD in their 40th year. However dementia may not develop until up to a decade later and some people remain cognitively intact. In this competitive renewal we propose to continue following (and expand) our cohort of aging adults with DS as well as recruit younger individuals to establish the role of white matter (WM) integrity losses cerebrovascular dysfunction (CVF) and neuroinflammation on cognitive decline. Aim 1 will continue to cognitively characterize a cohort of adults with DS and follow individuals for a period of 5 years as well as recruit a younger cohort that is pre-AD pathology. Magnetic resonance imaging (MRI) using diffuse tensor imaging will be used to track losses in WM integrity. Aim 2 will use MRI methods to detect cerebrovascular dysfunction by susceptibility weighted imaging fluid attenuated inversion recovery and arterial spin labeling. Aim 3 will use magnetic resonance spectroscopy and blood biomarkers to detect neuroinflammation as a function of age AD neuropathology and declines in cognition. Aim 4 will measure proteins and RNA to reflect protein and RNA changes to determine the neurobiological mechanisms underlying losses in WM integrity CVF and shifts in neuroinflammation in the brains of autopsy cases with DS. We will be able to identify targets for intervention studies (Aim 4) that could be implemented to promote healthy brain aging and would result in cognitive (Aim 1) WM structural integrity (Aim 1) and CVF improvements (Aim 2) and reduced neuroinflammation (Aim 3) in future clinical trials. Identifying the earliest signsof dementia and indicators of individual variation in cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration.

project_terms:
Adult;Age;Age-Years;Aging;Alzheimer's Disease;Amyloid beta-Protein;Antigen-Antibody Complex;Attenuated;Autopsy;Behavior;Biological Markers;Blood;Brain;Case Series;Cerebrovascular Disorders;Chromosomes Human Pair 21;Classification;Clinical Trials;Cognition;Cognitive;Cognitive aging;Data;Dementia;Dependency;Development;Diagnosis;Diffuse;Down Syndrome;Employee Strikes;Encephalitis;Event;Future;Genes;Goals;Hereditary Disease;Human;Image;Impaired cognition;Individual;Inflammation;Inflammatory;Intellectual functioning disability;Intervention Studies;Link;Liquid substance;Longitudinal cohort;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Mediating;Molecular;Molecular Target;Nerve Degeneration;Neurobiology;Neurofibrillary Tangles;Outcome;Parietal Lobe;Pathology;Pathway interactions;Pattern;Phenotype;Plasma;Play;Predisposition;Proteins;Quality of life;RNA;Recovery;Recruitment Activity;Reporting;Research;Research Design;Role;Senile Plaques;Signal Transduction;Spin Labels;Syndrome;Testing;United States;United States National Institutes of Health;Variant;abeta accumulation;abeta deposition;age related;aging brain;brain tissue;cerebrovascular;clinical imaging;cognitive function;cohort;functional decline;imaging modality;improved;middle age;neurobiological mechanism;neuroinflammation;neuropathology;novel;prevent;public health relevance;virtual;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The proposed study will identify early changes in brain inflammation cerebrovascular dysfunction and white matter integrity losses that signal changes in cognition behavior and functioning reflecting Alzheimer disease (AD) in adults with Down syndrome (DS). Identifying the earliest signs of dementia and indicators of individual variation incognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration. .


application_id: 9212380
project_number: 1R56DA041201-01
project_title: Monoamine Uptake Inhibition for Cocaine Dependence: A Novel Drug Combination
administering_ic: NIDA
award_notice_date: 2016-04-06
opportunity_number: PA-13-338
application_type: 1
activity_code: R56
ic: DA
serial_number: 041201
program_official: HAMPSON, AIDAN
project_start_date: 2016-05-01
project_end_date: 2019-04-30
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant: Despite prevention and intervention efforts prevalence of cocaine (COC) use and dependence remains stable which suggests innovative strategies are needed like pharmacotherapy. COC blocks dopamine (DAT) serotonin (SERT) and norepinephrine (NET) transporters. COC addiction is characterized by perturbations of these systems making monoamine uptake inhibition a logical target for medications development. Over 30 trials determined the efficacy of monoamine uptake inhibitors for COC dependence but only DA-SERT and NET inhibitors were effective in a majority of the trials in which they were tested. Continuing to target monoamine uptake inhibition is warranted but novel pharmacological strategies are needed to enhance efficacy. We propose to demonstrate the initial efficacy of an innovative pharmacological strategy for managing COC dependence: Triple Monoamine-Uptake Inhibition. Triple monoamine uptake inhibitors are under development but are not yet available for use with humans. Triple monoamine-uptake inhibition can; however be achieved by combining available medications. Duloxetine (DUL) an antidepressant has high affinity for the SERT and NET (ki = 0.8 and 7.5 nM respectively) but lower affinity for the DAT (ki = 240 nM). Methylphenidate (MTH) has high affinity for the DAT (ki = 34 nM) but lower affinity for the SERT and NET (ki = >10000 and 339 nM respectively). We will combine DUL and MTH to functionally produce a triple monoamine-uptake inhibitor. A mixed-model study will be conducted in which separate cohorts of non- treatment-seeking COC-dependent participants will be randomized to different maintenance doses of delayed- release DUL (i.e. DUL dose is a between-subject factor). Participants (N=16) in each DUL cohort will be maintained concurrently on long-acting MTH (i.e. MTH dose is a within-subject factor). The reinforcing effects of COC will be determined after participants in each DUL cohort are maintained for 4 days on each of the MTH doses (i.e. COC dose is also a within-subject factor). COC self-administration will be the primary outcome measure because the ability to attenuate the reinforcing effects of drugs is a reliable predictor of an effective pharmacotherapy.We hypothesize DUL-MTH combinations will produce an additive or supra-additive reduction in the reinforcing effects of COC relative to the constituent drugs alone. Innovations include: 1) testing a novel strategy triple monoamine-uptake inhibition; 2) testing a combination of marketed drugs as opposed to waiting for compounds under development to be available for use in humans thereby quickly impacting clinical research; 3) the use of once-daily dosing formulations of DUL and MTH which will improve compliance when advanced to clinical trials; 4) the use of a sophisticated drug self-administration procedure; 5) testing multiple doses of DUL and MTH alone and in combination to identify the optimal dose combination to enhance the probability of success when advanced to a clinical trial; and 6) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of DUL-MTH combinations.

project_terms:
12 year old;Accounting;Admission activity;Affinity;American;Anhedonia;Antidepressive Agents;Attention deficit hyperactivity disorder;Attenuated;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Data;Dependence;Development;Disease;Dopamine;Dose;Formulation;Goals;Health;Human;Inpatients;Laboratory Study;Maintenance;Measures;Methylphenidate;National Institute of Drug Abuse;Norepinephrine;Outcome Measure;Participant;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Physiological;Placebos;Prevalence;Preventive Intervention;Probability;Procedures;Public Health;Questionnaires;Randomized;Reporting;Research;Research Design;Safety;Self Administration;Serotonin;Study models;System;Testing;United States;addiction;clinical practice;cocaine use;cohort;double-blind placebo controlled trial;drug market;duloxetine;improved;indexing;inhibitor/antagonist;innovation;monoamine;novel;novel drug combination;novel strategies;primary outcome;success;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The research proposed in this application will determine the initial efficacy safety and tolerability of a novel drug combination duloxetine and methylphenidate as a pharmacotherapy for cocaine dependence. A rigorous inpatient human laboratory study will be conducted. The proposed study is innovative and important because it will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate the efficacy of duloxetine-methylphenidate combinations for managing cocaine dependence.


application_id: 9212179
project_number: 5R01HL074185-13
project_title: Reversing diabetic muscle myopathy by exercise and exosomes
administering_ic: NHLBI
award_notice_date: 2017-01-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 074185
program_official: SCHWARTZ, LISA
project_start_date: 2003-09-05
project_end_date: 2019-01-31
study_section: Special Emphasis Panel[ZRG1-MOSS-C(02)S]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Although exercise mitigates diabetic complications and myopathy the mechanism is unclear. The long-term goal of this project is to understand the mechanism of diabetic myopathy. Studies from previous funding period revealed causative role of endothelial-myocyte (E-M) uncoupling in cardiomyopathy. The connexin -37 and -43 are associated with endothelial and myocyte coupling; and mitochondria contains connexin-43. Matrix metalloproteinase-9 (MMP-9) disrupts connexins and is activated in diabetes unequivocally. Interestingly the exercise decreases MMP-9 activity. Exosomes 50-100 nm nanovesicles contain mir-RNAs and are released from myocytes. In this renewal application we will determine the role of exercise-mediated release in exosome containing mir-RNAs that mitigates the endothelium-myocyte myocyte-myocyte and mitochondrial-myocyte uncoupling by down regulating the MMP-9. The central hypothesis of this proposal is that MMP-9 degrades connexins and causes endothelial-myocyte myocyte-myocyte and mitochondria-myocyte uncoupling in diabetes. Exercise releases exosomes containing mir-RNAs that decreases MMP-9 and mitigates uncoupling. We will test the central hypothesis by following three specific aims. Specific aim #1: To determine whether the exercise releases exosomes that contain mir-29b mir-323 mir-455 and mir-466 which negatively regulate MMP-9 and mitigate fibrosis and uncoupling. Specific aim #2: To determine whether endothelial-myocyte uncoupling is caused by perivascular/pericapillary fibrosis and myocyte-myocyte uncoupling is caused by interstitial fibrosis in diabetes and exercise mitigates these conditions. Specific aim #3: To determine whether the dys-synchronization of mitochondrial fusion-fission causes mitochondria-myocyte uncoupling (mitochondrial remodeling) in diabetes and exercise alleviate. To evaluate the release of exosomes and their effect on MMP-9 and consequently Cx-37 and Cx-43 adult male db/db and controls db/+ wild type (WT-C57 and FVB) mice MMP-9 KO db/db/MMP-9 DKO Cx-37-Tg db/db/Cx-37-Tg; Cx-43-Tg and db/db/Cx-43-Tg mice with and without exercise will be used. Plasma and cardiac tissue exosomes will be isolated by ultracentrifugation/exoquick and characterized by electron microscopy/FACS/MACS. The levels of mir466 mir455 mir29b mir323 will be determined by RT-PCR and in situ hybridization. These studies will determine the mechanism of muscular structural functional and mitochondrial remodeling and exosomal therapeutic ramifications for diabetic myopathy.

project_terms:
3' Untranslated Regions;Acetylcholine;Adult;Adverse effects;Binding;Blood capillaries;Cardiac;Cardiomyopathies;Chimeric Proteins;Clinical Trials;Collagen;Complications of Diabetes Mellitus;Connexin 43;Connexins;Consumption;Coupling;Cytosol;Diabetes Mellitus;Electron Microscopy;Endothelium;Exercise;Extravasation;FVB Mouse;Fibrosis;Funding;Gelatinase B;Goals;Hybrids;In Situ Hybridization;Label;Laboratories;Measures;Mediating;MicroRNAs;Mitochondria;Mus;Muscle;Muscle Cells;Myocardial Infarction;Myopathy;Nitroprusside;PECAM1 gene;Perivascular Fibrosis;Plasma;Preparation;Proteins;Reverse Transcriptase Polymerase Chain Reaction;Role;Sirius Red F3B;Swelling;Techniques;Testing;Therapeutic;Tissues;Ultracentrifugation;capillary;connexin 37;cytochrome c;diabetic;exosome;inhibitor/antagonist;innovation;interstitial;male;nanovesicle;public health relevance;response;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Because cardiac matrix is unique general matrix metalloproteinase-9 (MMP-9) inhibitors may not mitigate the cardiac remodeling (Clinical trial- PREMIER-Pevention of Myocardial Infarction Early Remodeling using the MMP-9 inhibitor PG-116800). Exosomes that carry microRNAs can provide alternate treatment strategy to inhibit MMP-9 since exosomes are non-immunogenic and have no side effects. Myocyte releases exosomes and exosomes contains miRNA. The miRNA inhibits MMP- 9 by binding to the 3'UTR region. These studies will determine the mechanism of muscular structural functional and mitochondrial remodeling and exosomal therapeutic ramifications for diabetic myopathy.


application_id: 9212124
project_number: 5F31CA196219-03
project_title: Erbin-mediated regulation of colon cancer progression
administering_ic: NCI
award_notice_date: 2017-02-17
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: CA
serial_number: 196219
program_official: SCHMIDT, MICHAEL K
project_start_date: 2015-03-03
project_end_date: 2018-01-31
study_section: Special Emphasis Panel[ZRG1-F09B-B(20)L]
contact_pi_person_id: 12351385
contact_pi: STEVENS, PAYTON D
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Approximately 136000 new cases and 50310 deaths are predicted for the year 2014; this mortality is predominantly due to metastasis to other organs. If advances are to be made in the survival of colorectal cancer patients a better understanding of the molecular mechanisms involved in CRC metastasis is required. In this proposed study I plan to investigate the role of Erbin a basolateral-localized scaffolding protei in inhibiting CRC invasion and metastasis. This proposal centers on a novel discovery that Erbin plays an important role in suppressing epithelial-mesenchymal transition (EMT) of CRC cells by controlling cell polarity. The proper establishment of epithelial polarity allows cells to sense an respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Increasing evidence has suggested that disruption of this cellular polarity promotes the malignant progression of cancer cells. However the molecular mechanism underlying polarity regulation in the initiation and progression of CRC remains largely unknown. In my preliminary experiments I have found that knockdown of Erbin induces an EMT-like phenotype and promotes migration in CRC cells. In addition silencing Erbin resulted in the disruption of cell polarity in 3D cultures mislocalization of EGF receptors (EGFRs) and an increase in the activation of EGFR signaling. To begin to elucidate the underlying molecular mechanism we identified PHLPP a novel tumor suppressor in CRC as an interacting protein of Erbin. Interestingly loss of Erbin expression resulted in an increase in both Akt and ERK activation similar to that observed in PHLPP knockdown cells. I hypothesize that Erbin serves as a scaffolding protein bringing PHLPP in close proximity with its substrates. This interaction between PHLPP and Erbin could provide the spatial-temporal control necessary to suppress oncogenic Akt and RAS/RAF signaling. Furthermore the analysis of Erbin mRNA expression in two large sets of CRC patient samples revealed that Erbin is significantly down regulated in cancer specimens compared to normal controls thus supporting the role of Erbin as a tumor suppressor in CRC. In light of our preliminary findings the central hypothesis driving this proposal is that Erbin plays a critical role in inhibiting CRC metastasis and it functions by maintaining cell polarity to inhibit Akt- and RAS/RAF-mediated oncogenic signaling. The following specific aims are proposed: 1) to define the functional effects of Erbin in inhibiting CR invasion and metastasis. We will elucidate the molecular mechanism by which loss of Erbin promotes CRC invasion and metastasis both in vitro and in vivo; 2) to determine the role of Erbin in regulating PHLPP-dependent inhibition of Akt and RAS/RAF pathways. Defining the role of Erbin in tumor metastasis will have sustained impact on improving CRC patient care. Working on this project I will not only gain more research experience but also master the problem solving and communication skills needed to fulfill my career goals.

project_terms:
AKT inhibition;Automobile Driving;Binding Proteins;Cancer Center;Cancer Etiology;Cell Polarity;Cells;Cessation of life;Characteristics;Colon Carcinoma;Colorectal Cancer;Communication;Complex;Data;ERBB2 gene;Epidermal Growth Factor Receptor;Epithelial;Epithelial Cells;Event;Goals;Growth;Homeostasis;Human;In Vitro;Knowledge;Leucine-Rich Repeat;Light;Maintenance;Malignant - descriptor;Malignant Neoplasms;Mediating;Mentors;Mesenchymal;Molecular;Neoplasm Metastasis;Oncogenic;Organ;Outcome;Pathway interactions;Patient Care;Phenotype;Play;Problem Solving;Prognostic Marker;Protein Family;Protein phosphatase;Proteins;Publishing;RAF1 gene;RAS inhibition;Ras/Raf;Receptor Signaling;Regulation;Research;Role;Sampling;Scaffolding Protein;Signal Pathway;Signal Transduction;Specimen;Structure-Activity Relationship;Substrate Interaction;Testing;Tissues;Training;Tumor Suppressor Proteins;United States;base;cancer cell;career;cell motility;cell transformation;collaborative environment;colon cancer patients;epithelial to mesenchymal transition;experience;experimental study;improved;in vivo;insight;knock-down;mRNA Expression;member;migration;mortality;mouse model;novel;outcome forecast;prevent;public health relevance;scaffold;skills;spatiotemporal;three dimensional cell culture;tumor;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 142000 new cases and 51000 deaths are predicted for the year 2014; this mortality is predominantly due to metastasis to systemic organs. A better understanding of the molecular events leading to cancer metastasis is needed in order to improve the treatment and prognosis of CRC patients. Our studies we will focus on elucidating the functional importance of a novel tumor suppressor Erbin in preventing metastasis in CRC.


application_id: 9211870
project_number: 1P20GM121327-01
project_title: Project 4: The Role of Fatty Acid Synthase in Colorectal Cancer
administering_ic: NIGMS
award_notice_date: 2017-02-27
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 121327
study_section: Special Emphasis Panel[ZGM1 RCB-6 (CI)]
subproject_number: 7099
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-12-01
budget_end_date: 2017-11-30
project_abstract:
PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). My long-termgoal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis byunderstanding how changes in de novo fatty acid synthesis contribute to metastatic disease. Fatty acidsynthase (FASN) a key enzyme of de novo lipid synthesis is significantly upregulated and activated in CRCand its activity is associated with poor prognosis higher risk of disease recurrence and death. I have identifiedFASN as a potential target for advanced stages of disease and showed that upregulation of this enzyme is akey mechanism supporting metastasis in CRC. However the underlying mechanisms of regulation ofmetastasis by FASN are not understood. The current application proposes a comprehensive research plan tostudy novel mechanisms of regulation of growth survival and metastasis by FASN in CRC. Our preliminarystudies show that overexpression of FASN is associated with an increase in cellular respiration including -oxidation inhibition of autophagy and accumulation of lipid droplets. Therefore in Aim 1 we will elucidate therole of FASN in reprogramming of metabolic pathways and lipid storage in order to maintain energyhomeostasis and promote survival of cancer cells. Furthermore our preliminary data suggest that the primaryproduct of de novo fatty acid synthesis palmitate is selectively used for sphingolipid synthesis andoverexpression of FASN increases the level of sphingosine-1-phosphate (S1P) a bioactive sphingolipidknown to enhance migration and invasion of cancer cells. Therefore in Aim 2 we will test the hypothesis thatFASN promotes metastasis via activation of sphingosine kinases and an increase in S1P signaling. Finally inAim 3 we will test the effect of FASN inhibitor on proliferation in CRC patient-derived xenografts (PDXs) as amonotherapy and in combination with an autophagy inhibitor and identify potential biomarkers associated withCRC responsiveness to FASN inhibition. I will utilize biological samples from patients human primary cells and PDX models which are the mostadvanced models for pre-clinical target and drug evaluations. These models will be used in conjunction withstate-of-the-art approaches including Stable Isotope-Resolved Metabolomics (SIRM) to evaluate the effect ofFASN overexpression on cancer metabolism. The differential expression of FASN in normal versus cancercells makes de novo lipogenesis a desirable target for therapeutic intervention. I anticipate that the proposedwork will identify a subset of CRC patients who would benefit from targeted FASN inhibition and furtheradvance our understanding of the role of FASN in CRC that would potentially lead to the development of noveltherapeutic strategies to treat this disease.

project_terms:
Alpha Cell;Autophagocytosis;Biological;Biological Sciences;Cancer Cell Growth;Cancer Center;Cause of Death;Cell Proliferation;Cell Respiration;Cell Survival;Cells;Cessation of life;Characteristics;Colorectal Cancer;Data;Development;Disease;Disease-Free Survival;Drug Evaluation;Energy Supply;Enzymes;Evaluation;Fatty Acids;Fatty-acid synthase;Goals;Growth;Homeostasis;Human;Incidence;Kentucky;Lead;Link;Lipids;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Membrane;Metabolic;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Metastatic to;Modeling;Molecular;Neoplasm Metastasis;Oncogenic;Outcome;Palmitates;Patients;Play;Post-Translational Protein Processing;Pre-Clinical Model;Process;Production;Proteins;Publishing;Recurrence;Regulation;Research;Resected;Role;SPHK1 enzyme;Sampling;Signal Transduction;Solid Neoplasm;Sphingolipids;Sphingosine;Stress;Testing;Therapeutic;Therapeutic Intervention;Tumor Angiogenesis;Universities;Up-Regulation;Work;Xenograft Model;Xenograft procedure;antitumor effect;base;cancer cell;cancer survival;colon cancer cell line;colon cancer patients;differential expression;disorder risk;high risk;in vivo;inhibition of autophagy;inhibitor/antagonist;inorganic phosphate;knock-down;lipid biosynthesis;metabolomics;migration;molecular marker;novel;novel therapeutics;outcome forecast;overexpression;oxidation;potential biomarker;prevent;sphingosine 1-phosphate;sphingosine kinase;stable isotope;targeted treatment;tumor;tumor growth;tumor metabolism


application_id: 9211869
project_number: 1P20GM121327-01
project_title: Project 3: Role of RORa in Breast Cancer Metastasis
administering_ic: NIGMS
award_notice_date: 2017-02-27
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 121327
study_section: Special Emphasis Panel[ZGM1 RCB-6 (CI)]
subproject_number: 7098
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-12-01
budget_end_date: 2017-11-30
project_abstract:
PROJECT SUMMARYTumors have been described as wounds that do not heal. Similarities between tumors and wounds includetraits such as loss of polarized tissue structure and chronic inflammation. We showed that disruption of tissuepolarity induced activation of the NF-B pathway and macrophage infiltration. However little is known of howdisruption of epithelial cell polarity induces the NF-kB pathway and macrophage infiltration. We have identifiedthe RAR-related orphan nuclear receptor  (ROR) as a potent tumor suppressor by analyzing global geneexpression profiles in polarized and non-polarized mammary epithelial cells. Our recent findings show thatROR inhibits NF-B activation and macrophage infiltration in the syngeneic mouse mammary tumor model.These results suggest that ROR is a potent suppressor of macrophage infiltration in mammary epithelial cells.We found that knockdown of ROR significantly induced ROS production in mammary epithelial cells. Reactiveoxygen species (ROS) is a driver of cancer progression and a critical regulator of the NF-B pathway. Basedon these novel findings the central hypothesis of our proposal is that downregulation of ROR in non-polarizedbreast cancer cells induces ROS-dependent NF-B activation thereby enhancing macrophage infiltration anddifferentiation in cancer tissue. We will integrate high-throughput metabolic analysis and global geneexpression profiling to delineate mechanisms by which ROR inhibits ROS production. The long-term goal ofthis proposal is to define the impact of the ROR/NF-B axis in mediating mammary epithelial cell-macrophagecrosstalk and regulating breast cancer progression. We have proposed following specific aims to test thehypothesis: The first aim is to elucidate the molecular mechanisms by which ROR inhibits the NF-B pathwayin polarized acinus; the second aim is to determine how reduced ROR expression in non-polarized breastcancer cells induces macrophage infiltration and differentiation; and the third aim is to define the impact ofROR in suppressing breast cancer formation and metastasis. This proposed study involves in-depthmechanistic molecular biochemical and cellular studies using state-of-the art metabolomics imagingtechniques and model systems. The results will establish a novel link between disruption of tissue polarity andmacrophage infiltration/differentiation a critical gap in scientific knowledge in this important research area.Expected study outcomes will also provide new insights in function and regulation of the NF-B pathway duringbreast cancer development and progression that will facilitate the development of mechanistic based target forcancer therapy.

project_terms:
Acinus organ component;Antibodies;Area;Arginine;Biochemical;Biological Assay;Biological Models;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Breast Epithelial Cells;Breast cancer metastasis;Cancer Center;Cell Polarity;Centers of Research Excellence;Chronic;Coculture Techniques;Coupled;Development;Disease;Down-Regulation;Epithelial Cells;Event;Gene Expression;Gene Expression Profiling;Goals;Human;Imaging Techniques;Infiltration;Inflammation;Kentucky;Knockout Mice;Knowledge;Link;Malignant Neoplasms;Mammary gland;Mass Spectrum Analysis;Mediating;Metabolic;Methylation;Molecular;Molecular Profiling;Mus;NF-kappa B;Neoplasm Metastasis;Nuclear Orphan Receptor;Outcome Study;Oxidative Phosphorylation;Pathway interactions;Production;Protein-Arginine N-Methyltransferase;Reactive Oxygen Species;Regulation;Research;Role;Structure;TP53 gene;Testing;Tissue Microarray;Tissues;Transgenic Mice;Transplantation;Tumor Suppressor Proteins;Universities;base;cancer prevention;cancer subtypes;cytokine;experimental study;extracellular;in vivo;insight;knock-down;macrophage;malignant breast neoplasm;metabolomics;novel;stable isotope;targeted cancer therapy;trait;tumor;tumor metabolism;tumor progression


application_id: 9211868
project_number: 1P20GM121327-01
project_title: Project 2: Functional Role of the Serine Biosynthesis Pathway in Basal-like Breast Cancer
administering_ic: NIGMS
award_notice_date: 2017-02-27
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 121327
study_section: Special Emphasis Panel[ZGM1 RCB-6 (CI)]
subproject_number: 7097
contact_pi_person_id: 11716117
contact_pi: WU, YADI
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-12-01
budget_end_date: 2017-11-30
project_abstract:
PROJECT SUMMARYBasal-like breast cancer (BLBC) is one of the most aggressive forms of human cancer because it lackseffective targeted therapies and presents with development of recurrence distant metastasis shorter survivaland usually occurs in young women. BLBC has the activated epithelial-mesenchymal transition (EMT)program which provides cancer cells with the phenotypic and cellular plasticity required for invasion cancerstem cell (CSC)-like features and drug resistance. In the last several years we have systematically studiedthe role of Snail and Twist two key EMT-inducers in BLBC. We discovered that Snail functions to repressgenes that prevent EMT (such as E-cadherin) whereas Twist by interacting with BRD4 serves as atranscription activator to induce genes that enhance EMT (such as Wnt5A). We also discovered that EMT iscoupled with a metabolic reprogramming which provides a metabolic growth advantage for BLBC cells. Ourmetabolic analyses clearly indicate that BLBC cells also have increased activity for the pathway driving denovo serine synthesis which is a significant branch derived from glycolysis. The serine biosynthetic pathway isintimately coupled to one-carbon metabolism which intertwines with the folate and methionine cycles tointegrate nutritional inputs from glucose amino acids and vitamins for the biosynthesis of nucleotides lipidsand proteins as well as the methylation of chromatin. Our laboratory has discovered that phosphoserineaminotransferase 1 (PSAT1) expression a key enzyme in serine biosynthesis is markedly increased in celllines and clinical BLBC samples. In addition we found that expression of Twist correlated with the level ofPSAT1 in BLBC and that Twist significantly induced PSAT1 expression. Knockdown of PSAT1 expression notonly reduced glucose uptake and lactate production but also inhibited cell proliferation migration and invasionin BLBC. We hypothesize that Twist is the key molecule controlling the expression of PSAT1 which isresponsible for the elevated activity of the serine biosynthetic pathway seen in BLBC. Guided by strongpreliminary data we will test this hypothesis by pursuing three specific aims: (1) to elucidate the regulatorymechanism of PSAT1 by Twist in BLBC; (2) to delineate the function of the serine/PSAT1 pathway in BLBC;and (3) to determine the function of the serine/PSAT1 pathway in vivo. Our proposal is innovative andsignificant because it incorporates a merged investigation of two essential cancer markers in BLBC metabolicreprogramming and EMT and because it leads to the development of an effective precision cancer therapyapproach in treating BLBC by combining metabolic drugs with epigenetic inhibitors.

project_terms:
Amino Acids;Anabolism;Antioxidants;Automobile Driving;Brain;Breast Cancer Cell;Breast Cancer cell line;Bromodomain;Cancer Center;Carbon;Cell Line;Cell Proliferation;Centers of Research Excellence;Chromatin;Clinical;Coupled;Data;Development;Disease;Distant Metastasis;Drug resistance;E-Cadherin;Enzymes;Epigenetic Process;Epithelial;Folic Acid;Folic Acid Antagonists;Fructose;Genes;Glucose;Glycolysis;Goals;Grant;Growth;Human;Intrinsic factor;Investigation;Kentucky;Laboratories;Lung;Maintenance;Malignant Neoplasms;Mediating;Mesenchymal;Metabolic;Metabolic Pathway;Metabolism;Methionine;Methylation;Molecular;Mus;Neoplasm Metastasis;Nucleic Acids;Nucleotide Biosynthesis;Nutritional;Pathway interactions;Patients;Pemetrexed;Pharmaceutical Preparations;Phenotype;Phosphoserine aminotransferase;Production;Protein Biosynthesis;Recurrence;Repression;Role;Sampling;Serine;Signal Transduction;Snails;Specificity;Specimen;Testing;Transcription Coactivator;Universities;Warburg Effect;Xenograft Model;aerobic glycolysis;base;cancer biomarkers;cancer cell;cancer stem cell;cancer therapy;cell growth;glucose uptake;in vivo;inhibitor/antagonist;innovation;knock-down;lipid biosynthesis;malignant breast neoplasm;migration;neoplastic cell;novel therapeutic intervention;outcome forecast;overexpression;prevent;programs;targeted treatment;tumor;tumor metabolism;tumor microenvironment;vitamin biosynthesis;young woman


application_id: 9211867
project_number: 1P20GM121327-01
project_title: Project 1: The Role of Vitamin D in Protecting Against Cachexia in Cancer Patients
administering_ic: NIGMS
award_notice_date: 2017-02-27
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 121327
study_section: Special Emphasis Panel[ZGM1 RCB-6 (CI)]
subproject_number: 7096
contact_pi_person_id: 10544123
contact_pi: THOMAS, DAVID TRAVIS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-12-01
budget_end_date: 2017-11-30
project_abstract:
PROJECTSUMMARYVitamin D repletion is linked to improved muscle mitochondrial function lipid deposition and preservation;however while vitamin D insufficiency is common in cancer the mechanistic effects of vitamin D on musclemetabolic health in cancer patients have not been studied. This is important to address because cancercachexiaischaracterizedbymarkedmusclewastinganabolicresistanceectopicfatinfiltrationmitochondrialdysfunctionandcontributestodecreasedsurvival.Withnovelstrategiestoaddressthisknowledgegapwewilluse a combination of advanced metabolic analytical approaches with complementary model systems in cellculture and human subjects to understand the biochemical and physiological mechanisms underlying cancercachexia in relation to the role of Vitamin D in conjunction with resistance exercise (RE). By combininganalysesofmusclesizeandlocaltissuehemodynamicsinvivometabolomicsanalysesofmuscletissueandisolated mitochondria and changes in anabolic cell signaling lipid metabolism and oxidative capacity ofprimary muscle cells in vitro we will identify mechanisms underlying muscle response to vitamin D repletion.Our previous findings together with data that exercise improves muscle vitamin D storage and retrievalsuggest that vitamin D repletion synergizes with RE to improve muscle metabolic function and proteinsynthesis. Our overall objective is to examine mitochondrial function and anabolic resistance as potentialtargets of action of vitamin D on muscle metabolism size and strength in preventing the progression ofcachexia. The aims of this study are to: 1) non-invasively quantify lipid redistribution local muscle tissuemetabolismandmusclemassandstrengthofcancerpatientsbeforeandafter12weeksofvitaminDrepletionwithexerciseandproteinsupplementation(VitD)comparedtoexerciseandproteinsupplementationonly(Ctl);2) determine differences in muscle mitochondrial function in live tissue biopsied from human gastrocnemiusfrom VitD compared to Ctl; and 3) identify mechanisms whereby vitamin D and exercise regulate muscleanabolicsignalingandmitochondrialactivityinprimaryhumanmyotubecultures.Ourcentralhypothesisisthatvitamin D promotes muscle lipid availability for -oxidation in response to exercise thereby preventinglipotoxicityinthemuscleandpotentiallyimprovinganabolicsensitivityinmuscleduringcancercachexia.Theimpact of this project the first nutrition and exercise study designed as an inexpensive intervention is tounderstand the effect of vitamin D on the metabolic and anabolic dynamics which underpin dysfunction incachecticmuscle.IfvitaminDpromoteslipidpartitioningmusclemetabolicfunctionand/oranabolicsensitivitytheseadaptationswillultimatelyimprovecancertherapybycombatingcancercachexia.Furtherdiffuseopticalspectroscopy techniques have the potential to identify the minimum effective intervention dose for optimizingmetabolichealthleadingtomorepracticalandindividualizedlifestyleprescriptionstoreducehealthcarecosts.

project_terms:
Address;Amino Acids;Biochemical;Biological Preservation;Biopsy;Cachexia;Calcitriol;Cancer Center;Cancer Patient;Caprylates;Cell Culture Techniques;Consumption;Coupled;Data;Defect;Deposition;Dietary Intervention;Dietary Proteins;Diffuse;Dose;Elderly;Energy Metabolism;Enrollment;Exercise;Fatty acid glycerol esters;Fiber;Functional disorder;Gastrocnemius Muscle;Glucose;Glutamine;Health;Health Care Costs;Human;Hybrids;In Vitro;Infiltration;Intervention;Kentucky;Knowledge;Lead;Life Style;Link;Lipids;Magnetic Resonance Imaging;Maintenance;Malignant Neoplasms;Measures;Mentorship;Metabolic;Metabolism;Mitochondria;Modeling;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;Optics;Outcome;Oxygen;Patients;Periodicity;Physical activity;Physiological;Population;Protein Biosynthesis;Proteins;Research Design;Resistance;Retrieval;Role;Signal Transduction;Spectrum Analysis;Stem cells;Stretching;Supplementation;System;Techniques;Testing;Tissues;Translating;Universities;Vitamin D;cancer cachexia;cancer therapy;combat;effective intervention;functional improvement;hemodynamics;human subject;improved;in vivo;lipid metabolism;metabolomics;mitochondrial dysfunction;mitochondrial metabolism;muscle form;muscle metabolism;muscle strength;novel strategies;nutrition;oxidation;prevent;resistance exercise;response;spectroscopic imaging;stable isotope;standard of care;tumor metabolism


application_id: 9211866
project_number: 1P20GM121327-01
project_title: Core C: Imaging Core
administering_ic: NIGMS
award_notice_date: 2017-02-27
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 121327
study_section: Special Emphasis Panel[ZGM1 RCB-6 (CI)]
subproject_number: 7095
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-12-01
budget_end_date: 2017-11-30
project_terms:
Achievement;Address;Aging;Area;Bioinformatics;Biological Sciences;Biomedical Research;Biometry;Cancer Center;Cellular Structures;Centers of Research Excellence;Clinical;Color;Complex;Computer software;Consult;Consultations;Development;Disease Progression;Distant;Equipment;Evaluation;Extramural Activities;Faculty;Floor;Fluorescence;Focal Adhesions;Goals;Health Services Accessibility;Image;Image Analysis;Imaging Device;Imaging Techniques;Individual;Kentucky;Laboratories;Laboratory Research;Lasers;Link;Malignant Neoplasms;Metabolic;Metabolism;Methodology;Methods;Microscope;Mission;Monitor;NCI Center for Cancer Research;Neoplasm Metastasis;Organ;Pathology;Pilot Projects;Positioning Attribute;Preparation;Proteins;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Role;Sampling;Scanning;Scientist;Services;Slide;System;Time;Tissues;Training;Transfection;Universities;analytical tool;anticancer research;cancer therapy;career development;cost;cost effective;design;digital;experimental study;imaging capabilities;imaging modality;imaging system;in vivo imaging system;instrument;instrumentation;live cell imaging;metabolomics;microscopic imaging;multidisciplinary;novel;skills;success;tumor;tumor initiation;tumor metabolism;tumor microenvironment;tumorigenesis


application_id: 9211864
project_number: 1P20GM121327-01
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2017-02-27
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 121327
study_section: Special Emphasis Panel[ZGM1 RCB-6 (CI)]
subproject_number: 7093
contact_pi_person_id: 11045331
contact_pi: VANDERFORD, NATHAN LANE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-12-01
budget_end_date: 2017-11-30
project_abstract:
PROJECT SUMMARY The University of Kentucky (UK) Center for Cancer and Metabolism (CCM) will be established as a uniquemultidisciplinary Center of Biomedical Research Excellence (COBRE) designed to develop and deploy astrategically designed sustainable center infrastructure that cultivates cutting-edge research focused on therole of metabolic dysregulation in cancer development and progression. The Administrative Core providescritical scientific and administrative leadership to advance the goals of the CCM: to develop and sustain athematically focused multidisciplinary center infrastructure dedicated to defining the role of metabolism in thedevelopment and treatment of cancer and to use this novel platform to develop promising early-stageinvestigators with enhanced skills in an exciting new area of cancer research. The goal of the AdministrativeCore is to enhance the scientific productivity of the center's faculty by delivering efficient administrativeservices across scientific projects and cores as well as pilot projects through an organizational/leadershipframework that supports flexible team-based mentoring and provides for clear accountability. Thus the CCMAdministrative Core is the central coordinating hub responsible for integrating highly complementarydisciplinary strengths at UK in cancer metabolism and data sciences and leveraging sophisticatedmetabolomics tools and advanced cancer imaging capabilities. The core has primary responsibility for realizingthe CCM's scientific vision operating on principles grounded in transformational leadership and sharedadministrative oversight. Administrative Core functions will be operationalized through the following threespecific aims: 1) to provide coordinated operational management of the center; 2) to facilitate and coordinateresearch training mentoring and career development activities to develop early-stage investigators in cancerand metabolism and expand research in this area through pilot projects; and 3) to coordinate and conductoverall planning and evaluation. The core will coordinate and implement all administrative activities of theCCM: oversee daily center activities; coordinate program communications fiscal processes meetingorganization and advisory committee input; facilitate and expedite interactions among projects and cores;manage the pilot project program; and lead program and project evaluation efforts. The core will oversee atotal of four current projects two cores and a biostatistics and bioinformatics support component and ensurehighly effective well-planned team-based mentorship including basic and clinical perspectives and externalexpertise for all early-stage investigators.

project_terms:
Accountability;Address;Administrator;Advanced Malignant Neoplasm;Advisory Committees;Area;Arts;Biochemistry;Bioinformatics;Biomedical Research;Biometry;Cancer Center;Cardiovascular Diseases;Centers of Research Excellence;Clinical;Clinical Sciences;Communication;Communication Programs;Coupled;Data Science;Development;Effectiveness;Ensure;Evaluation;Faculty;Fostering;Funding;Goals;Health;Health Sciences;Institutes;Kentucky;Knowledge;Lead;Leadership;Malignant Neoplasms;Mediator of activation protein;Medicine;Mentors;Mentorship;Metabolic;Metabolism;Molecular Medicine;Monitor;Obesity;Oncogenic;Oral;Pilot Projects;Play;Process;Productivity;Program Evaluation;Public Health;Research;Research Infrastructure;Research Personnel;Research Training;Resource Sharing;Resources;Role;Science;Scientist;Seasons;Senior Scientist;Services;System;Systemic disease;Translational Research;United States National Institutes of Health;Universities;Vision;anticancer research;base;biomedical informatics;cancer therapy;career development;college;design;flexibility;imaging capabilities;improved;meetings;metabolomics;multidisciplinary;next generation;novel;programs;skills;stable isotope;success;synergism;therapeutic target;tool;tumor metabolism


application_id: 9211863
project_number: 1P20GM121327-01
project_title: University of Kentucky Center for Cancer and Metabolism
administering_ic: NIGMS
award_notice_date: 2017-02-27
opportunity_number: PAR-14-035
application_type: 1
activity_code: P20
ic: GM
serial_number: 121327
program_official: LIU, YANPING
project_start_date: 2017-03-01
project_end_date: 2021-12-31
study_section: Special Emphasis Panel[ZGM1 RCB-6 (CI)]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ZHOU, BINHUA P
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Apoptosis;Area;Attention;Basic Science;Biochemistry;Bioinformatics;Biological Markers;Biology;Biometry;Cancer Center;Cancer Death Rates;Cancer Patient;Cell Cycle;Cell Proliferation;Cell Survival;Centers of Research Excellence;Clinical;Collaborations;Core Facility;Coupled;Data;Data Science;Development;Discipline;Early Diagnosis;Environment;Event;Faculty;Fostering;Foundations;Funding;Future Generations;Goals;Grant;Growth;Image;Incidence;Interdisciplinary Study;Intervention;Investigation;Kentucky;Lead;Link;Location;Malignant Neoplasms;Mediator of activation protein;Mentors;Metabolic;Metabolic Diseases;Metabolism;Neoplasm Metastasis;Obesity;Outcome;Oxidation-Reduction;Pilot Projects;Proliferating;Quality of life;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Role;Scientist;Seeds;Signal Transduction;System;Therapeutic;Training;Translations;United States National Institutes of Health;Universities;anticancer research;base;cancer cell;cancer imaging;cancer initiation;cancer therapy;career;cohesion;defined contribution;design;imaging capabilities;improved;innovation;insight;interdisciplinary approach;metabolomics;mortality;multidisciplinary;novel;novel therapeutics;prevent;programs;skills;success;synergism;therapeutic target;therapy outcome;tool;trait;tumor metabolism;tumor microenvironment;tumor progression;tumorigenesis


application_id: 9211335
project_number: 5R01ES025515-03
project_title: Oxidative stress Cr(VI) carcinogenesis and prevention
administering_ic: NIEHS
award_notice_date: 2017-01-23
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 025515
program_official: SHAUGHNESSY, DANIEL
project_start_date: 2015-05-01
project_end_date: 2020-01-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: ZHANG, ZHUO
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cr(VI) is well known environmental carcinogen. Its mechanism of action or prevention remains to be investigated. Our preliminary studies have shown that exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) generates reactive oxygen species (ROS) which are responsible for Cr(VI)-induced cell transformation. After transformation these cells exhibit constitutive expressions of Nrf2 and its target antioxidant proteins resulting in decreased ROS generation. The constitutive expression of Nrf2 activates Bcl-2 through binding of Nrf2 to antioxidant responsive element (ARE) of Bcl-2 gene promoter leading to increased survival and tumorigenicity of these transformed cells. These preliminary studies indicate that in non-transformed cells activation of Nrf2 may decrease ROS generation thus inhibit Cr(VI)-induced cell transformation. In contrast in Cr(VI)-transformed cells inactivation of constitutive expression of Nrf2 may decrease Bcl-2 and increase ROS leading to inhibitions of survival and tumorigenicity of transformed cells. We have screened various natural compounds attempting to select those with two properties: (a) to activate Nrf2 and decrease ROS in non- transformed cells to prevent Cr(VI)-induced cell transformation and (b) to inhibit constitutive expression of Nrf2 and enhance ROS and apoptosis in Cr(VI)-transformed cells to prevent tumorigenesis. We have found that luteolin a natural compound has such dual properties. The central hypothesis is that luteolin protects Cr(VI)- induced carcinogenesis both by inducing transient activation of Nrf2 in non-transformed cells resulting in inhibition of Cr(VI-induced cell transformation and by inactivating constitutive expression of Nrf2 in Cr(VI)- transformed cells resulting in inhibitions of survival and tumorigenesi of Cr(VI)-transformed cell and angiogenesis. Aim 1 will study prevention of luteolin against Cr(VI)-induced cell transformation. We will study luteolin-induced activations of Nrf2 and its target antioxidant genes and decreases of Cr(VI)-generated ROS. The integration of these molecular events is likely to be responsible for protection of luteolin against Cr(VI)- induced cells transformation. Aim 2 will demonstrate that in Cr(VI)-transformed cells luteolin is able to inhibit constitutive expressions of Nrf2 increase ROS level and decrease survival and tumorigenicity of Cr(VI)- transformed cells. The protection of luteolin against Cr(VI)-induced angiogenesis in animal exposed to Cr(VI) via drinking water will also be investigated. Aim 3 will investigate protection o luteolin against Cr(VI)-induced carcinogenicity in CD1 mice using a recently established animal model of "whole-life" chronic metal exposure. The animals will be exposed to Cr(VI) in the presence and absence of luteolin via drinking water in the whole life time from breeding to adulthood. The roles of Nrf2 and its key target will be studied. Tumors will be assessed in the offspring up to 2 years of adulthood. The proposed study will not only gain novel mechanistic insight in Cr(VI) carcinogenesis but also have potential translational impact of using chemopreventive compounds targeting Nrf2 signaling pathway to combat Cr(VI)-induced carcinogenicity.

project_terms:
2 year old;Adult;Animal Model;Animals;Antioxidants;Apoptosis;Apoptotic;BCL2 gene;Binding;Breeding;Cell Death;Cells;Chemopreventive Agent;Chronic;Data;Development;Diet;Elements;Environmental Carcinogens;Enzymes;Epithelial;Event;Exhibits;Exposure to;Female;Gene Expression;Gene Targeting;Generations;Genes;Lactation;Life;Literature;Lung;Luteolin;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Metal exposure;Molecular;Mus;Nutritional;Occupational;Oncogenic;Oxidative Stress;Pathway interactions;Precancerous Conditions;Pregnancy;Premalignant;Prevention;Prevention strategy;Property;Proteins;Reactive Oxygen Species;Resistance;Role;Signal Pathway;Signal Transduction;Source;Stress;Superoxide Dismutase;Time;Tumor Tissue;Tumorigenicity;Up-Regulation;angiogenesis;cancer cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;combat;drinking water;epidemiology study;exposed human population;in vivo;insight;male;novel;offspring;pregnant;prevent;promoter;public health relevance;translational impact;tumor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    NARRATIVE The study will show that luteolin protects Cr(VI) carcinogenesis by activation of inducible Nrf2 in pre-malignant stage to prevent cell transformation and by inactivation of constitutive expression of Nrf2 in later stage to prevent tumorigenesis. The expected results will demonstrate the roles of oxidative stress and Nrf2 in the mechanism of Cr(VI) carcinogenesis and the strategy for prevention.


application_id: 9211223
project_number: 5R01HD075829-03
project_title: The development of emotion processing in infancy
administering_ic: NICHD
award_notice_date: 2017-01-16
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 075829
program_official: FREUND, LISA S
project_start_date: 2015-04-01
project_end_date: 2020-02-29
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 8534513
contact_pi: BHATT, RAMESH S
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Emotion processing is a critical component of social functioning. Adults derive a considerable amount of emotion information from body posture and movement. In some circumstances bodies are better sources of emotion cues than faces. Yet virtually nothing is known about the development of emotion processing from body gestures. This is in contrast to a great number of studies that have examined facial emotion processing. The proposed studies are aimed at filling this gap. They will examine predictions from models of body knowledge development emotion processing and action understanding while documenting the nature of development in early infancy and examining mechanisms that drive development. Slaughter and Heron's model of body knowledge development proposes that visuospatial body knowledge is minimal early in life and slow to develop in comparison to facial knowledge. In contrast other models of body knowledge development and theories of action understanding and emotion processing envision early development of knowledge about bodies and emotions signaled by them. One set of studies will contrast these predictions. Another set of studies will address a significant debate in the emotion literature concerning whether knowledge about basic categories of emotions is available early in life. A third set of proposed studies will test the hypothesis that visual exploration capacities contribute to the development of body emotion knowledge. Another group of studies will examine the proposition that motor experience and development are associated with body emotion knowledge development. The fifth set of proposed studies originates from empirical findings and theoretical propositions suggesting that learning plays a significant role in the development of object and social perception. We will test the hypothesis that body emotion knowledge development is facilitated by learning induced by observing exemplars of emotional behavior and correlations between bodily facial and vocal emotional expressions. Thus the proposed studies will document the development of body emotion knowledge in infancy examine the role of visual exploration as an underlying mechanism of development and investigate whether motor development and observational learning contribute to this development. Many developmental disorders such as Autism are at least in part based on deficits in emotion processing. The proposed research will contribute to the analyses and treatment of such disorders by documenting the nature of emotion processing from body information in infancy and the manner in which it normally develops early in life.

project_terms:
Address;Adult;Affect;Age-Months;Age-Years;Anger;Autistic Disorder;Awareness;Behavior;Categories;Conduct Disorder;Cues;Development;Disease;Emotional;Emotions;Face;Feeling;Fright;Gestures;Human;Human body;Infant;Infant Development;Intention;Knowledge;Learning;Life;Literature;Mental disorders;Modality;Modeling;Motor;Movement;Nature;Organism;Perception;Perceptual learning;Persons;Play;Posture;Psychopathology;Research;Role;Scanning;Signal Transduction;Social Functioning;Social Interaction;Social Perception;Source;Testing;Visual;Visuospatial;Walkers;Work;autism spectrum disorder;base;cognitive function;developmental disease/disorder;emotional behavior;experience;infancy;negative affect;object perception;public health relevance;research study;showing emotion;social engagement;theories;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Many disorders such as Autism Spectrum Disorder and Conduct Disorder are at least in part based on deficits in emotion processing. Some of these disorders manifest themselves quite early in life while the psychopathology associated with others may be caused by developmental deficits. It is thus important to understand the development of emotion processing. The proposed research will contribute to the analysis and treatment of psychological disorders by documenting the nature of emotion processing from body information in infancy and the manner in which it normally develops early in life.


application_id: 9210590
project_number: 5R25AA022823-04
project_title: Basic and Applied Summer Training in Alcohol Research
administering_ic: NIAAA
award_notice_date: 2017-01-09
opportunity_number: PAR-13-104
application_type: 5
activity_code: R25
ic: AA
serial_number: 022823
program_official: POWELL, ELIZABETH
project_start_date: 2014-02-01
project_end_date: 2019-01-31
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 1869834
contact_pi: NIXON, KIMBERLY
other_pis: PRENDERGAST, MARK A
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky Summer Training in Alcohol Research (STAR) program provides 12 weeks of intensive hands-on alcohol research for 11 outstanding undergraduate students. A broad range of research opportunities exist that are truly bench to bedside because of the breadth of empirical approaches employed by our alcohol research faculty. Research topics available to the trainees range from the cell biology of alcohol neurodegeneration to applied survey research on the role that alcohol may have in moderating interpersonal domestic violence. This program will mesh well with the long-standing existing infrastructure of the Department of Pharmaceutical Science's summer undergraduate research program. Trainees will perform independent research under the supervision of alcohol research faculty participate in weekly educational and professional development seminars and be trained in responsible conduct of research. Hard work discovery and great science will culminate in a research presentation to faculty laboratory personnel and peers at our annual Summer Alcohol Research Symposium. Aggressive advertising of the program through scientific organizations networking websites and directly to regional liberal arts colleges undergraduate institutions and especially those schools serving underrepresented groups in STEM fields will allow for the recruitment of a diverse pool of summer undergraduate trainees. In concert with the main goals of providing hands on experience in basic and applied alcohol research we will be promoting the biomedical and behavioral sciences as career choices for these students. Evaluations of short-term and long-term successes of the STAR program on our primary objective of increasing the pool of diverse applicants to graduate programs and biomedical research careers will be conducted and followed throughout the years of the program.

project_terms:
Advertising;Alcohol consumption;Alcohols;Arts;Behavioral Sciences;Biomedical Research;Brain Injuries;Career Choice;Cellular biology;Development;Domestic Violence;Engineering;Evaluation;Faculty;Goals;Institution;Kentucky;Laboratories;Laboratory Personnel;Mathematics;Nerve Degeneration;Pharmacologic Substance;Play;Recruitment Activity;Research;Research Infrastructure;Role;STEM field;Schools;Science;Students;Supervision;Surveys;Technology;Training;Underrepresented Groups;Universities;Work;addiction;alcohol research;bench to bedside;career;college;experience;faculty research;peer;programs;public health relevance;responsible research conduct;scientific organization;success;summer research;symposium;undergraduate research;undergraduate student;web site

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The University of Kentucky Basic and Applied Summer Training in Alcohol Research (STAR) is a 12 week summer research program for 11 undergraduates to work hands on in the laboratory of faculty pursuing a broad spectrum of alcohol and addiction-related research questions. These research experiences range in focus from the cell biology of alcohol-induced brain damage to role that alcohol use/abuse plays in interpersonal domestic violence. This program aims to attract and develop a diverse pool of qualified experienced applicants for graduate study and/or careers in science technology engineering or math fields.


application_id: 9210134
project_number: 5R21NS096670-02
project_title: Mitochondrial Transplantation Strategies to Promote Recovery after Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2017-03-20
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: NS
serial_number: 096670
program_official: JAKEMAN, LYN B
project_start_date: 2016-04-01
project_end_date: 2019-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 6146950
contact_pi: RABCHEVSKY, ALEXANDER GEORGE
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The current proposal is designed to develop of a new research area that is aimed at transplanting mitochondria into the injured rodent spinal cord as a therapeutic strategy following traumatic spinal cord injury (SCI). We and others have found that maintaining normal mitochondrial bioenergetics after contusion SCI fosters both neuroprotection and functional recovery. However no studies have examined the effects of transplanting exogenous mitochondria into spinal cord tissue after injury in an attempt to normalize overall cellular bioenergetics and spare adjacent host tissues. Accordingly this new line of investigations will test ultimately whether transplanting exogenous healthy mitochondria into the injured spinal cord promotes functional neuroprotection. Using a rat model of contusion SCI we have preliminary data showing that allogeneic transgenically-labeled (turboGFP) mitochondria derived from PC12 cells microinjected around the injury site maintain overall cellular bioenergetics assessed 24 hrs later. Moreover using confocal microscopy to evaluate specific antibodies to both inner and outer mitochondrial membranes we have preliminary evidence that grafted turboGFP mitochondria integrate within nave and injured spinal cord tissues. Based on these seminal findings we propose to conduct a series of transplantation strategies to deliver mitochondria around the injury sites. The ultimate goal is to identify a potential autologous cell source of mitochondria (i.e. leg muscle) to prevent secondary tissue injury that is mediated in large part by mitochondrial loss and dysfunction. In summary Aim 1a will comparatively employ a dose-response approach to assess whether transplanted MitoTracker Red-labeled mitochondria isolated from muscles are equally effective as allogeneic turboGFP mitochondria on cellular bioenergetics and the extent of inflammation following acute contusion SCI. Aim 1b will then assess comparatively the frequency and distribution of labeled mitochondria incorporated into host cells over the first week post-injury. Finally Aim 2 will establish whether transplantation of muscle-derived mitochondria increases long-term tissue sparing and recovery of hindlimb locomotion following SCI. This project has translational potential wherein mitochondria notably autologous can be transplanted around the injury site to spare penumbral tissues. Based on the collective expertise of the PI in cellular transplantation into injured spinal cord tissue and both Co-Is in bioenergetic assessments and mitochondrial-targeted therapeutics for neurotrauma along with our preliminary feasibility data there are no foreseen technical obstacles to successfully carry out this project. Notably future experiments stemming from the results of the current proposal will be designed to test delayed grafting paradigms to extend a more clinically relevant therapeutic time window for transplantation of mitochondria to promote functional recovery in more chronic SCI models.

project_terms:
Acute;Allogenic;Animals;Antibodies;Area;Astrocytes;Autologous;Behavioral;Bioenergetics;Cell Culture Techniques;Cells;Chronic;Complement;Confocal Microscopy;Data;Dose;Endothelial Cells;Fixatives;Fostering;Frequencies;Functional disorder;Future;Goals;Hindlimb;Histological Techniques;Histology;Homeostasis;Image;Immunohistochemistry;Inflammation;Injectable;Injury;Investigation;Knowledge;Label;Leg;Limb structure;Locomotion;Locomotor Recovery;Measures;Mediating;Microglia;Mission;Mitochondria;Modeling;Multienzyme Complexes;Muscle;Nervous System Trauma;Neurons;Oligodendroglia;Outer Mitochondrial Membrane;Oxidative Stress;Oxygen Consumption;PC12 Cells;Process;Rattus;Recovery;Recovery of Function;Research;Research Proposals;Respiration;Rodent;Seminal;Series;Site;Soleus Muscle;Source;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Subcellular Fractions;Techniques;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Transplantation;Traumatic injury;United States National Institutes of Health;base;cell type;clinically relevant;comparative;design;dosage;experimental study;gait examination;improved;inflammatory marker;injured;innovation;insight;muscle transplantation;nano;neuroprotection;novel therapeutic intervention;novel therapeutics;prevent;public health relevance;response;stem;targeted treatment;trend

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The current proposal is an innovative research plan to determine for the first time whether intraspinal transplantation of healthy mitochondria acutely after contusion spinal cord injury (SCI) results in improved sparing of host tissue and functional recovery. The knowledge gained from the proposed experiments will provide direct insight into the potential of this novel therapeutic intervention to maintain cellular bioenergetics while reducing both oxidative stress and inflammation following acute SCI. The planned research is relevant to aspects of the NIH's mission to discover new therapies for SCI by utilizing seminal mitochondrial transplantation techniques to provide neuroprotection manifested in improved long-term behavioral recovery.


application_id: 9210097
project_number: 5R01ES024757-03
project_title: Coal Ash and Neurobehavioral Symptoms in Children Aged 6-14 Years Old.
administering_ic: NIEHS
award_notice_date: 2017-01-24
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 024757
program_official: GRAY, KIMBERLY A
project_start_date: 2015-05-01
project_end_date: 2020-01-31
study_section: Behavioral Genetics and Epidemiology Study Section[BGES]
contact_pi_person_id: 8476117
contact_pi: ZIEROLD, KRISTINA MARIE
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Coal ash is generated when power plants burn coal for energy. Coal ash is not classified as a hazardous waste so there are no federal regulations that govern its use storage or disposal. Most coal ash is stored in open landfills or in ponds. There are over 800 coal ash storage sites in the U.S. and many are located near residential communities. Coal ash includes many components but fly ash which is comprised of small spherical particles is the greatest component. Composition of fly ash varies but it frequently contains toxic metals (e.g. arsenic cadmium chromium copper lead manganese and mercury) polycyclic aromatic hydrocarbons (PAHs) and radioactive elements. Neurobehavioral disorders in children are associated with exposure to many of the metals that are contained in fly ash. Thus children exposed to fly ash are potentially at risk of developing neurobehavioral disorders. Children are exposed to fly ash via inhalation and ingestion from fugitive dust emissions that come off the landfills and the ponds.  This project will investigate the effect of fy ash on children who live in neighborhoods near two coal ash storage sites in Louisville Kentucky. Some children live in homes within 150 feet of coal ash landfills and ponds. Working with neighborhoods within 10 miles of the coal ash storage sites we will complete four specific aims: (1) Characterize indoor exposure from fly ash and heavy metals in homes of children residing near coal ash store sites compared to children living further away from coal ash storage sites (2) Determine if the heavy metal body burden differs from children residing near coal ash storage sites compared to children living further away from storage sites (3) Assess if increased fly ash exposure and greater heavy metal body burden is associated with poorer neurobehavioral performance and more neurobehavioral symptoms (4) Utilize mapping spatial analysis and modeling applications of geographic information systems (GIS) for household recruitment analysis of distance decay effects surface interpolation of Aims 1 and 2 results and fate and transport modeling of fly ash.  Three hundred and sixty children aged 6-14 will be recruited for this study. Neurobehavioral performance will be tested using the Behavioral Assessment Research System and neurobehavioral symptoms will be assessed by the Child Behavior Checklist (CBCL). Any child who has a CBCL t score =7 will be further assessed through a Structured Clinical Interview for the Diagnosis of DSM Disorders (SCID). Environmental sampling in the homes will be completed to determine the presence of fly ash and metals. Toenail samples will be collected from the children and analyzed for heavy metals. Questionnaires and an in-home assessment will help to characterize environmental exposure history and health history of the children. The results will provide evidence to define the environmental health impact of coal ash.

project_terms:
14 year old;Area;Aromatic Polycyclic Hydrocarbons;Arsenic;Attention deficit hyperactivity disorder;Autistic Disorder;Behavior Disorders;Behavior assessment;Blood Circulation;Body Burden;Breathing;Burn injury;Cadmium;Caliber;Child;Child Behavior Checklist;Chromium;Chronic;Clinical;Coal;Communities;Copper;Developmental Delay Disorders;Diagnosis;Disease;Dust;Emotional disorder;Environmental Exposure;Environmental Health;Exposure to;Focus Groups;Geographic Information Systems;Hazardous Substances;Hazardous Waste;Health;Heavy Metals;Home environment;Household;Human;Ingestion;Interview;Kentucky;Lead;Learning;Low income;Lung;Manganese;Mercury;Metals;Methods;Modeling;Neighborhoods;Neurobehavioral Manifestations;Neurotoxins;Parents;Participant;Particle Size;Performance;Population;Power Plants;Principal Investigator;Property;Public Health;Questionnaires;Radioactive Elements;Recording of previous events;Recruitment Activity;Regulation;Research;Research Personnel;Residual state;Risk;Sampling;Site;Structure;Structure of nail of toe;Surface;Surveys;Symptoms;Testing;Time;Toxic effect;United States;aged;base;coal ash;community partnership;exposure pathway;fly ash;follow-up;foot;hazard;improved;indoor exposure;junior high school;landfill;neurobehavioral;neurobehavioral disorder;neurotoxic;particle;pollutant;public health relevance;remediation;systems research;toxic metal

public_health_relevance:
PUBLIC HEALTH RELEVANCE: An estimated 1.54 million children in the U.S. are exposed to coal ash yet the research investigating the health impacts from exposure is scarce. Children exposed to coal ash which is comprised of small particles containing multiple heavy metals are potentially at risk for developing neurobehavioral symptoms. This study which will be the first todocument coal ash exposure heavy metal body burden and neurobehavioral performance and symptoms in children may provide evidence of the environmental and health impact of coal ash.


application_id: 9210076
project_number: 5R01DK056132-14
project_title: Neural Circuitry in the Dorsal Vagal Complex
administering_ic: NIDDK
award_notice_date: 2016-12-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 056132
program_official: HYDE, JAMES F
project_start_date: 2001-06-01
project_end_date: 2020-01-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Diabetes mellitus is a major health concern affecting nearly 26 million people in the United States. Serious complications resulting from diabetes including include heart disease stroke hypertension blindness nervous system damage and autonomic dysfunction. A major impediment to developing successful diabetes treatments (versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant systems that contribute to control of metabolic homeostasis. This proposal investigates disease-related plasticity of central neural circuitry involved in autonomic control including control of blood glucose homeostasis. Experiments utilize murine models of type 1 and type 2 diabetes. Preautonomic neurons of the dorsal vagal complex which contains second-order viscerosensory neurons in the nucleus tractus solitarius (NTS) and preganglionic parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) are glucosensors and also contribute significantly to autonomic regulation of glucose homeostasis. Vagal motor output is suppressed in diabetes leading to autonomic dysregulation including excess hepatic glucose production and gastric motility dysfunction. Preliminary results show that GABA neurons in the NTS in particular are responsive to elevated glucose. Paradoxically GABAA receptor-mediated responses in the DMV are persistently enhanced in a model of type 1 diabetes in a manner consistent with maintenance of prolonged hyperglycemia. Some but not all of these responses are preserved in a type 2 diabetes model suggesting a form of GABA receptor plasticity that mediates the decreased vagal output seen in diabetes. In addition modulation of GABA receptors in the dorsal vagal complex has a significant effect on blood glucose levels and this effect is hypothesized to be enhanced in diabetic mice versus controls. This proposal aims to determine the causes and underlying features of the recently-discovered diabetes-induced plasticity of the GABAergic system in the vagal complex. Electrophysiological recordings from vagal complex neurons in slices from control and diabetic mice will be used to obtain functional cellular data related to altered GABAergic inhibition changes associated with diabetes development in the streptozotocin-treated mouse a model of type 1 diabetes and the TallyHo mouse a model of type 2 diabetes. Aim 1 will determine insulin- and glucose- dependence of enhanced tonic GABA currents in diabetic mice aim 2 will identify cellular mechanisms contributing to diabetes-associated GABA receptor plasticity in the DMV and aim 3 will determine the effects of GABA receptor modulation in the dorsal vagal complex on systemic glucose homeostasis. Results will guide future studies aimed at disease-modifying therapies from a systemic standpoint based on modulating specific inhibitory neural functions in the brainstem to address diabetes-related autonomic dysregulation in patients.

project_terms:
Abdomen;Address;Affect;Animal Model;Area;Autonomic Dysfunction;Blindness;Blood Glucose;Brain;Brain Stem;Cell Nucleus;Chronic;Complex;Data;Dependence;Development;Diabetes Mellitus;Diabetic mouse;Disease;Dorsal;Electrophysiology (science);Functional disorder;Future;GABA Receptor;Gastrointestinal tract structure;Genetic Transcription;Glucose;Goals;Health;Heart Diseases;Hepatic;Homeostasis;Human;Hyperglycemia;Hyperinsulinism;Hypertension;Insulin;Insulin-Dependent Diabetes Mellitus;Knowledge;Liver;Maintenance;Mediating;Metabolic Control;Modeling;Modification;Molecular;Motor Neurons;Motor output;Mus;Nervous System Trauma;Neurons;Neurophysiology - biologic function;Non-Insulin-Dependent Diabetes Mellitus;Organ;Output;Pancreas;Pathology;Patients;Peripheral;Physiological;Play;Regulation;Role;Slice;Stomach;Streptozocin;Symptoms;Synapses;System;Testing;United States;Viscera;Visceral;Whole Blood;base;blood glucose regulation;cell motility;diabetes mellitus therapy;diabetic;dorsal motor nucleus;experimental study;gamma-Aminobutyric Acid;gastrointestinal;glucose metabolism;glucose production;mouse model;nerve supply;neural circuit;public health relevance;receptor;response;stroke;symptom treatment;trafficking;type I diabetic

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Preganglionic parasympathetic neurons in the vagal complex innervate the abdominal organs and critically regulate whole blood glucose metabolism. These neurons are sensitive to elevated glucose and undergo long-lasting changes in synaptic excitability in animal models of diabetes. The proposed experiments will examine mechanisms underlying diabetes-associated inhibition changes in the vagal complex that represent reactive responses to chronic hyperglycemia and/or hyperinsulinemia which may contribute to disease pathology and symptoms. The eventual goal of informing future studies aimed at treating pathologies underlying diabetes.


application_id: 9208063
project_number: 5R01NS089324-03
project_title: Functional consequences of silencing propriospinal pathways after SCI in the adult rat
administering_ic: NINDS
award_notice_date: 2017-01-23
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 089324
program_official: JAKEMAN, LYN B
project_start_date: 2015-02-01
project_end_date: 2020-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: WHITTEMORE, SCOTT R
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits many of the physiological details of those circuits and their contributions to functional recovery following spinal cord injury (SCI) remain t be determined. Recent development of powerful molecular tools enables functional dissection of neural circuitry by selectively and temporarily silencing neurotransmission. We will focus on two classes of spinal cord interneurons that have been described anatomically but remain a mystery functionally. These are the long-ascending propriospinal neurons (LAPNs) and the long descending propriospinal neurons (LDPNs) that together comprise a population we have termed "inter-enlargement" because they provide direct and indirect connections between the cervical and lumbar enlargements. The LAPNs and LDPNs are assumed to play critical roles in forelimb-hindlimb coordination in quadrupeds and to coordinate arm-swing and upper body-lower body movements in people. We hypothesize that LAPNs and LDPNs provide detailed temporal information about the step cycle and limb movement to the corresponding enlargement and thus play critical roles in forelimb-hindlimb coordination in the normal adult rat and in functional recovery following a contusive SCI. This proposal will directly test these hypotheses. Strong preliminary data unequivocally support the rationale of this proposal. Specifically: Aim 1 will determine the role of LAPNs/LDPNs in locomotion as we will independently silence these pathways bilaterally ipsilaterally and commissurally. Sophisticated gait and kinematic analyses as well as terminal histological analyses will be used to quantify functional deficits. Aim 2 will determine the role of LAPNs/LDPNs in recovered function after SCI. These pathways will be silenced after functional recovery has plateaued following two different injury severities. Aim 3 will determine the role of LAPNs/LDPNs in the process of functional recovery after SCI. LAPN/LDPN networks will be silenced 3-10 and 28-35 days post-SCI time periods of initial weight bearing and stabilization of locomotor function respectively. Collectively the proposed experiments will hopefully delineate how these pathways may be therapeutically targeted for functional recovery after SCI.

project_terms:
Address;Adult;Anatomy;Animals;Behavior;Behavioral;Bilateral;Cells;Cervical;Contusions;Data;Development;Dissection;Doxycycline;Elements;Excision;Forelimb;Gait;Grant;Hindlimb;Histologic;Injectable;Injury;Interneurons;Ipsilateral;Locomotion;Locomotor Recovery;Lumbar Regions;Molecular;Motor Activity;Movement;Neural Pathways;Neurons;Neurotransmitters;Outcome;Pathway interactions;Phenotype;Physiological;Play;Population;Presynaptic Terminals;Process;Rattus;Recovery;Recovery of Function;Role;Severities;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Subfamily lentivirinae;Synaptic Transmission;System;Testing;Tetracycline Control;Therapeutic;Time;Virus;Walking;Weight-Bearing state;Work;anterograde transport;arm;central pattern generator;drinking water;experimental study;insight;kinematics;limb movement;neural circuit;neurotransmission;neurotropic;novel;public health relevance;retrograde transport;therapeutic target;tool;vector;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This grant examines the role of the long ascending and descending propriospinal neurons (LAPNs LDPNs) in the inter-enlargement control of forelimb hindlimb coordination. Using a novel two virus vector system we can transiently silence these neural pathways and examine the effects on both normal walking behavior and their contribution to functional recovery after spinal cord injury (SCI). Successful completion of the experiments outlined in this proposal would provide important insight in the potential for harnessing these pathways to enhance functional recovery after SCI.


application_id: 9207953
project_number: 1R21ES027391-01
project_title: Treatment of persistent chlorine-induced small airway disease
administering_ic: NIEHS
award_notice_date: 2016-09-23
opportunity_number: PAR-15-315
application_type: 1
activity_code: R21
ic: ES
serial_number: 027391
program_official: NADADUR, SRIKANTH
project_start_date: 2016-09-30
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1 MDCN-B (55)]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of thepossibility that it could be released in industrial accidents or terrorist attacks. Acute effects of chlorineinhalation include dyspnea hypoxemia pneumonitis and pulmonary edema. Longer term consequences ofchlorine inhalation include both pulmonary function impairment and structural changes that have beenobserved in some exposed individuals. Our collaborator Dr. Erik Svendsen has documented pulmonaryfunction abnormalities in a population of individuals who were exposed to chlorine as a result of a largeaccidental release that occurred in Graniteville SC in 2005. The results point to a spectrum of respiratorydisease states but suggest that an important component involves small airway disease. An impediment todeveloping countermeasures for persistent chlorine-induced lung disease is the lack of a relevant animalmodel for efficacy testing. Our preliminary data indicate that rabbits exposed to chlorine and examined 7days later exhibit inflammation of the small airways and develop sporadic obliterative lesions characteristic ofbronchiolitis obliterans (BO). These animals exhibited normal baseline lung resistance but exhibitedhyperreactivity to inhaled methacholine. Based on these preliminary data we propose to expand on thesestudies to develop a model in which the obliterative changes to small airways are more widespread resultingin increased baseline lung resistance as has been observed in humans exposed to chlorine gas. We willthen assess the efficacy of a potential countermeasure when administered following chlorine exposure forthe prevention of small airway disease. The hypotheses to be tested are: 1) Increasing post-exposuremonitoring time and/or chlorine dose will produce widespread small airway BO lesions that result insignificant increases in baseline lung resistance; and 2) Treatment with inhaled corticosteroid plus -adrenergic agonist after chlorine exposure will inhibit the development of BO lesions and abnormal lungfunction. Specific Aim 1 will be to develop an animal model of persistent chlorine-induced lung disease thatreplicates the disease states observed in chlorine-exposed humans. Specific Aim 2 will be to evaluate acurrently available therapy (inhaled corticosteroid plus long-acting -adrenergic agonist) in a rabbit model ofpersistent chlorine-induced lung disease. These exploratory studies will generate valuable informationtoward development of an appropriate animal model for countermeasure testing and will generate initial dataregarding efficacy of a type of treatment currently used for irritant-induced asthma that could be readilyadopted as a countermeasure.

project_terms:
Acute;Acute Lung Injury;Adopted;Adrenal Cortex Hormones;Adrenergic Agonists;Adverse effects;Affect;Airway Obstruction;Animal Model;Animals;Area;Asthma;Breathing;Bronchiolitis Obliterans;Characteristics;Chemicals;Chlorine;Chronic;Conscious;Data;Development;Disease;Dose;Dyspnea;Exhibits;Exposure to;Fibrosis;Genetic;Goals;Histologic;Hospitals;Human;Hypoxemia;Impairment;Individual;Industrial Accidents;Inflammation;Inflammatory;Investigation;Irritants;Length;Lesion;Long-Term Effects;Lung;Lung diseases;Methods;Modeling;Molecular;Monitor;Morbidity - disease rate;Mus;Oryctolagus cuniculus;Pathology;Poisoning;Poisons;Population;Prevention;Pulmonary Edema;Pulmonary Inflammation;Pulmonary Pathology;Recording of previous events;Recovery;Research;Resistance;Respiratory physiology;Techniques;Terminal Bronchiole;Testing;Therapeutic;Time;Toxic effect;Trachea;Trees;Unconscious State;United States;Ventilator;acute symptom;base;chemical threat;chlorine gas;efficacy testing;injury and repair;interest;lung injury;methacholine;morphometry;novel;prevent;pulmonary function;repaired;research study;respiratory;respiratory health;small airways disease

public_health_relevance:
The goal of the proposed experiments is to develop novel ways to treat chronic airway disease caused byacute high level exposure to chlorine gas. This type of research is important because of concerns that U.S.civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals suchas chlorine.


application_id: 9207417
project_number: 5R21AI122894-02
administering_ic: NIAID
award_notice_date: 2017-01-27
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 122894
program_official: PESCE, JOHN T
project_start_date: 2016-02-01
project_end_date: 2019-01-31
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-02-01
project_title:
The cell cycle of T. gondii bradyzoites within tissue cysts:in vivo development of an HIV-AIDS opportunistic parasite

project_abstract:
DESCRIPTION (provided by applicant): Toxoplasmic encephalitis (TE) is one of the HIV-AIDS defining opportunistic infections that is associated with the reactivation of the chronic form of te infection mediated by bradyzoites within tissue cysts in the CNS. Despite the central role in thepathogenesis of HIV-AIDS associated toxoplasmosis little is known about the biology of tissue cysts and the bradyzoite stage of the parasite they contain. Among the key limitations in studying the progression of the chronic phase and the mechanisms by which latency is established maintained and lost during reactivation has been that rigorous insights into the physiology and development of bradyzoites in vivo has not been possible. Toward removing this major limitation we have initiated a comprehensive research program to understand bradyzoite biology by the development of approaches that directly address bradyzoite replication within tissue cysts in the in vivo context. These initial studies reveal that bradyzoites possess a previously unappreciated capacity for replication and metabolism that can be exploited in the development drugs to target what has been a traditionally refractory state. With the present study we aim to establish not only a new paradigm for bradyzoite biology but also develop the experimental methodologies to dissect bradyzoite replication we have been able to conclusively detect occurs challenging the existing dogma that bradyzoites are largely dormant entities. Our initial studies provide a new window into the dynamics of bradyzoite growth within tissue cysts which exhibit a level of complexity and sophistication that has not been previously appreciated. In this exploratory and developmental study we focus on the generation of new experimental approaches to directly interrogate and dissect the progression of the cell cycle within bradyzoites. Such insights would fill a vast gap in our knowledge that has stymied the development of treatments that are targeted toward the elimination of tissue cysts and bradyzoites. Targeting of tissue cysts and bradyzoites would eliminate the primary trigger of toxoplasmic encephalitis in the HIV-AIDS.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Animals;Biochemical;Biology;Blood;Bromodeoxyuridine;Cell Culture Techniques;Cell Cycle;Cell Cycle Progression;Cerebral Toxoplasmosis;Chronic;Chronic Phase;Cyst;Cytokinesis;DNA biosynthesis;Data;Development;Disease;Drosophila genus;Effectiveness;Encephalitis;Event;Exhibits;Exploratory/Developmental Grant;Foundations;Gene Expression;Generations;Growth;HIV;Human;Incidence;Infection;Knowledge;Label;Life;Life Cycle Stages;Maintenance;Meat;Mediating;Metabolic;Metabolism;Methodology;Methods;Molecular;Monitor;Natural immunosuppression;Nucleotides;Oocysts;Opportunistic Infections;Oral;Parasites;Parasitic infection;Pathogenesis;Patients;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Phase;Phosphotransferases;Physiology;Population;Positioning Attribute;Prevalence;Refractory;Regulation;Reporter;Research;Role;Serological;Signal Transduction;Source;Specificity;Standardization;System;Testing;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Work;base;drug development;high reward;high risk;imaging software;immunological status;in vivo;insight;latent infection;programs;public health relevance;therapy development;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: In spite of their central role in the pathogenesis of cerebral toxoplasmosis in HIV-AIDS the biology of bradyzoites and the tissue cysts within which they reside remain poorly understood. With this proposal apply newly developed approaches to directly investigate bradyzoite growth while defining their cell cycle within tissue cysts in vivo.This work fills a critical gap in our knowledge by applying mechanistic approaches to address fundamental questions of direct importance to the understanding of toxoplasma pathogenesis.


application_id: 9206453
project_number: 5U01AI123832-02
project_title: Role of TRPV1 in asthma exacerbation
administering_ic: NIAID
award_notice_date: 2016-11-25
opportunity_number: PA-13-302
application_type: 5
activity_code: U01
ic: AI
serial_number: 123832
program_official: MINNICOZZI, MICHAEL
project_start_date: 2016-01-15
project_end_date: 2018-12-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 1857989
contact_pi: LEE, LU-YUAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Inflammatory reaction is known to lead to an increase in tissue temperature but whether airway tissue temperature increases during asthma exacerbation is not yet known. Transient receptor potential vanilloid type 1 receptor (TRPV1) a ligand gated non-selective cation channel with a distinct sensitivity to heat is selectively and abundantly expressed in vagal bronchopulmonary C-fiber sensory nerves. A series of studies carried out in our lab have established the first evidence that an increase in temperature within the normal physiological range can activate and sensitize these TRPV1-expressing sensory neurons innervating the lung and airways; activation of these C-fiber afferents can elicit reflex bronchoconstriction cough and other airway defense responses. Indeed our recent study has demonstrated that an increase in airway temperature by hyperventilating humidified hot air triggered cough and bronchoconstriction in patients with mild and stable asthma but not in healthy subjects. The airway constriction was mediated through cholinergic reflex because it was completely prevented by pretreatment with ipratropium. The accompanying airway irritation and coughing further suggested an involvement of airway sensory nerves presumable TRPV1-expressing C-fiber afferents. In the light of these novel findings this proposed study aims to tes the following hypotheses: 1) in patients with allergic asthma the airway tissue temperature is elevated locally in the region when the inflammatory reaction is evoked by a segmental bronco-provocation with allergen. 2) Both the thermal sensitivity of these neurons and the expression of TRPV1 at the sensory nerve terminals are enhanced by chronic airway allergic inflammation. Thus a slight increase in local tissue temperature can lower the activation thresholds and enhance the sensitivity of TRPV1-expressing C-fiber sensory nerves in the airways of asthmatics. The synergistic effects of these factors may play a major part in the development of the airway hypersensitivity during chronic inflammation. This translational study will be performed in both asthmatic patients and in an animal model of allergic asthma. Results obtained from these studies should provide novel insights into the involvement of TRPV1 in the pathogenic mechanisms of airway hypersensitivity and help to uncover the mechanisms underlying the debilitating symptoms associated with airway inflammatory diseases.

project_terms:
Advanced Development;Afferent Neurons;Air;Allergens;Allergic inflammation;Animal Model;Asthma;Breathing;Bronchial Provocation Tests;Bronchial Spasm;Bronchoconstriction;C Fiber;Cations;Chronic;Coughing;Data;Development;Devices;Disease;Exhibits;Extrinsic asthma;Humidifier;Hyperventilation;Inflammation;Inflammation Mediators;Inflammatory;Institutional Review Boards;Ion Channel;Ipratropium;Irritants;Kentucky;Laboratories;Lead;Ligands;Lung;Measures;Mediating;Membrane;Mucous Membrane;Names;Neurons;Pathogenicity;Patients;Persons;Physiological;Pilot Projects;Play;Property;Protocols documentation;Rattus;Reaction;Reflex action;Reporting;Research;Research Personnel;Respiratory Signs and Symptoms;Respiratory System;Respiratory tract structure;Risk;Role;Sensory;Sensory Nerve Endings;Series;Technology;Teleconferences;Temperature;Testing;Tissues;Training;Universities;Vanilloid;Wisconsin;afferent nerve;airway hyperresponsiveness;allergic airway inflammation;associated symptom;asthmatic;asthmatic airway;asthmatic patient;cholinergic;clinically relevant;constriction;defense response;design;disabling symptom;experience;human subject;insight;irritation;novel;novel therapeutic intervention;prevent;public health relevance;receptor;response;sensor;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Airway hypersensitivity characterized by symptoms of airway irritation cough and bronchospasm is a hallmark feature of airway inflammatory diseases. This study is designed to test a novel hypothesis that a specific ion channel named TRPV1 present in the airway sensory nerves plays an important role in the airway hypersensitivity found in patients with allergic asthma. Results of this translational study to be conducted in both asthmatic patients and pulmonary sensory neurons isolated from an animal model of asthma will help to advance the development of new therapeutic strategies for alleviating these debilitating symptoms.


application_id: 9205218
project_number: 5R01CA165469-05
project_title: Role of Tcl1 and Par-4 in regulation of chronic lymphocytic leukemia
administering_ic: NCI
award_notice_date: 2017-01-20
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 165469
program_official: JHAPPAN, CHAMELLI
project_start_date: 2013-02-07
project_end_date: 2019-01-31
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 7739669
contact_pi: BONDADA, SUBBARAO
other_pis: RANGNEKAR, VIVEK M
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Chronic lymphocytic leukemia (CLL) also known as small cell lymphoma constitutes almost 30% of all cases of non-Hodgkin's lymphoma. It is the most common adult leukemia. Despite advances in chemotherapy treatment options for CLL patients are limited with only a modest efficacy especially for patients with unmutated types of B cell receptors (BCR) del (17p13.1) and p53 mutations. Tcl-1 an oncogene initially found to be translocated in T-cell leukemias has been found to be expressed at higher levels in CLL phenotypes that are classified as aggressive. A mouse model for CLL has been generated by expressing the Tcl-1 oncogene in B cells using immunoglobulin promoter and the E enhancer. These mice reproducibly develop CLL in 13-18 months and have been shown to be excellent models for human CLL. Par-4 is a pro-apoptotic tumor suppressor discovered by us that induces apoptosis in cancer but not normal cells using both the Fas pathway and by inhibiting NF-B. We made four novel observations. First the B-cell receptor signaling pathway is active both in the human CLL cells and in the E-Tcl-1 mouse model of CLL as reflected by constitutive activation of Src family protein tyrosine kinases (SFK). Second we discovered that expression of Tcl1 is down regulated upon inhibition of SFK suggesting a role for BCR signaling in Tcl1 expression. Third we found that expression of Par-4 is down-regulated in E-Tcl1 CLL cells compared to normal mice while its expression has been found to be variable in human CLL cells. Fourth we discovered that E-Tcl1 cells are killed by soluble Par-4 and SAC a specific domain of Par-4 that is cytotoxic only to tumor cells. Based on these observations we hypothesize that a balance between Tcl1 and Par-4 regulated by BCR signaling decides the fate of CLL cells between survival and death. We have three specific aims. Aim 1 will determine the importance of BCR signaling and the role of specific SFKs in the regulation of Tcl-1 and Par-4 expression using the E-Tcl-1 mouse model of CLL. Aim 2 will investigate the importance of Par-4 overexpression for CLL development using a newly generated inducible Par-4 transgenic mice mouse model and the E-Tcl-1 mice. Aim 2 will involve preclinical studies to test the efficacy of extracellular Par-4 and SAC to inhibit CLL growth in the E-Tcl-1 mouse model. The relative importance of Tcl-1 and Par-4 will be studied in Aim 3 with primary CLL cells from patients thus translating the basic research findings in Aims 1 and 2 to clinical samples. The collaboration between UK and OSU provides us an opportunity to integrate the basic science and pre-clinical findings from the first two Aims with studies in Aim 3 using patient derived CLL cells. The exciting aspect of these studies is the possibility that soluble Par-4 or SAC can be developed into a treatment strategy for CLL cells either in isolation or in combination with SFK inhibitors or other targets that are currently being investigated in our laboratories.

project_terms:
17p13.1;Affect;Animal Model;Apoptosis;Apoptotic;B lymphoid malignancy;B-Cell Lymphomas;B-Lymphocytes;Basic Science;Biology;Bone Marrow;Cell Survival;Cells;Cessation of life;Chromosomal translocation;Chronic Lymphocytic Leukemia;Clinical;Clinical Data;Clinical Investigator;Clinical Trials;Collaborations;Development;Disease;Down-Regulation;Elderly;Enhancers;Equilibrium;Experimental Leukemia;Family member;GRP gene;GRP78 gene;Genes;Goals;Grant;Growth;Human;Immunoglobulins;In Vitro;Induction of Apoptosis;Killings;Laboratories;Leukemic Cell;Lymphoid;Malignant Neoplasms;Mediating;Modality;Modeling;Mus;Mutation;Nature;Non-Hodgkin's Lymphoma;Oncogenes;Organ;PAWR gene;Pathway interactions;Patients;Peptides;Phenotype;Play;Predisposition;Protein Family;Protein Tyrosine Kinase;Proteins;Receptor Signaling;Receptors Antigen B-Cell;Regulation;Resistance;Role;Sampling;Signal Pathway;Signaling Molecule;Small Interfering RNA;Small-Cell Lymphoma;Surface;T-Cell Leukemia;T-Cell Receptor;T-Lymphocyte;TP53 gene;Testing;Therapeutic;Therapeutic Effect;Transcription Factor AP-1;Transgenic Mice;Transgenic Organisms;Translating;Tumor Suppressor Proteins;Western World;Whole Blood;adult leukemia;base;cancer cell;cell age;cell killing;chemotherapy;clinical development;clinically relevant;cytotoxic;efficacy testing;extracellular;genetic approach;in vivo;inhibitor/antagonist;member;molecular marker;mouse model;neoplastic cell;novel;novel therapeutics;outcome forecast;overexpression;peripheral blood;pre-clinical;preclinical study;pro-apoptotic protein;promoter;public health relevance;receptor;response;therapy development;treatment strategy;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The efficacy of existing therapeutic modalities for Chronic lymphocytic leukemias which affect mainly older adults is not high and new therapies for this disease are not yet available. The proposed studies will focus on two novel molecules Tcl-1 and Par-4 that have antagonistic roles in survival of CLL cells and may provide new avenues that can be developed into therapeutic strategies.


application_id: 9204860
project_number: 5R01NS084857-04
project_title: Carbonyl Scavenging for Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2017-01-16
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 084857
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2014-02-01
project_end_date: 2018-07-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our laboratory has documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and neurotoxic protein modification by binding of LP-derived carbonyl-containing aldehydes such as 4-hydroxynoneal (4-HNE) and acrolein to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). This oxidative damagecauses brain mitochondrial respiratory compromise and decreased calcium (Ca++) buffering which worsens post-TBI neuronal intracellular Ca++ overload calpain-mediated neuronal cytoskeletal degradation neurodegeneration and neurological impairment. Recently a novel antioxidant approach for post-central nervous system (CNS) injury for decreasing and possibly reversing oxidative damage has been identified that involves scavenging the LP-derived carbonyl compounds ("carbonyl scavenging") preventing their neurotoxic effects. Preliminary support from other laboratories and our own has shown that certain clinically used drugs that contain hydrazine function groups can covalently bind to 4-HNE or acrolein and prevent their neurotoxicity. The proposed 3 Aim project will employ phenelzine a long used hydrazine-containing anti-depressant that contains has been found to be an effective carbonyl scavenger as a tool to investigate the antioxidant neuroprotective effects of carbonyl scavenging in isolatedrat brain mitochondria and the rat controlled cortical impact TBI model. Specifcally the project will define the neuroprotective pharmacology (e.g. mechanism of action dose-response and therapeutic window) of phenelzine's "carbonyl scavenging" in terms of neuronal mitochondrial and cytoskeletal protection along with the ability to improve chronic motor and cognitive recovery and to decrease post-traumatic neurodegeneration. Since phenelzine has a long history of clinical use and a well understood human safety profile the translation of the drug's use into clinical TBI trials would be facilitated.

project_terms:
4 hydroxynonenal;Acrolein;Acute;Aldehydes;Antihypertensive Agents;Antioxidants;Binding;Brain;Brain Injuries;Buffers;Calcium;Calpain;Cell Culture Techniques;Cell membrane;Chemicals;Chronic;Clinical;Contusions;Data;Dose;Drug usage;Elements;Exposure to;Functional disorder;Generations;Histologic;Human;Hydralazine;Impairment;Injury;Ischemia;Laboratories;Lesion;Lipid Binding;Lipid Peroxidation;Lipid Peroxides;Lipids;Mediating;Membrane Lipids;Mitochondria;Mitochondrial Proteins;Modeling;Modification;Motor;Mus;Nerve Degeneration;Nervous system structure;Neurologic;Neuronal Injury;Neurons;Patients;Peroxonitrite;Pharmacology;Phase;Phase III Clinical Trials;Phenelzine;Polyunsaturated Fatty Acids;Post-Translational Protein Processing;Propane;Rattus;Reaction;Reactive Nitrogen Species;Reactive Oxygen Species;Recording of previous events;Regimen;Reperfusion Therapy;Reporting;Research Personnel;Safety;Spinal cord injury;Stress;Testing;Therapeutic;Time;Tissues;Toxic effect;Translations;Traumatic Brain Injury;Traumatic Subarachnoid Hemorrhage;Treatment Efficacy;Wood material;attenuation;axonal degeneration;base;carbonyl compound;carbonyl group;central nervous system injury;clinically relevant;cognitive function;cognitive recovery;controlled cortical impact;cytotoxic;improved;in vivo;injured;lipid peroxidation inhibitor;morris water maze;mortality;motor function improvement;motor recovery;nerve injury;neurotoxic;neurotoxicity;novel;oxidative damage;perhydroxyl radical;prevent;protective effect;public health relevance;respiratory;response;stroke;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project will examine the neuroprotective effects of phenelzine a long-used anti-depressant compound that has recently been discovered to also be a scavenger of lipid peroxidation-derived carbonyl-containing aldehydes such as 4-hydroxynonenal and acrolein in the rat controlled cortical impact traumatic brain injury model (CCI-TBI). Preliminary data has demonstrated that phenelzine can protect brain mitochchondria from impairment of their function an effect that is correlated with a lessened 4-hydroxynonenal modification of mitochondrial proteins and to decrease post-TBI brain damage. This proposal will expand our understanding of the neuroprotective pharmacology (e.g. mechanism of action dose-response and therapeutic window) of phenelzine's "carbonyl scavenging" in terms of neuronal mitochondrial and cytoskeletal protection along with the ability to improve chronic motor and cognitive recovery and to decrease post-traumatic neurodegeneration.


application_id: 9204411
project_number: 5R03DK107912-02
project_title: Vinyl chloride-NAFLD interaction
administering_ic: NIDDK
award_notice_date: 2016-12-07
opportunity_number: PAR-12-285
application_type: 5
activity_code: R03
ic: DK
serial_number: 107912
program_official: SASLOWSKY, DAVID E
project_start_date: 2016-01-15
project_end_date: 2018-05-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 10438358
contact_pi: BEIER, JULIANE I
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Obesity and its metabolic complications are highly prevalent and are major health problems in the United States and worldwide. Indeed obesity may influence individual susceptibility to other environmental exposures such as vinyl chloride (VC). Specifically we hypothesize that experimental NAFLD and the consumption of certain types of dietary fat such as poly-unsaturated fatty acids (PUFA) sensitize the liver to VC as a 2nd hit. We therefore propose that that LA metabolites sensitize the liver to VC hepatotoxicity via molecular organelle and cellular VC effects (NAFLD mechanisms). Aim 1. Evaluate the role of OXLAMs in VC-enhanced hepatocyte death in an animal model of NAFLD. Specifically we will: a) determine the dose response for NAFLD/NAFLD mechanisms following sub-acute VC exposures and the impact of co-exposures with HF/LA diets b) determine whether the ablation of OXLAMs via 12/15-LO genetic deficiency attenuates VC-induced liver inflammation and injury and the mechanisms involved. This work will be performed in vivo comparing wild-type (WT) to 12/15-LO knockout mice with complementary in vitro models that target 12/15-LO pharmacologically or genetically (e.g. primary cells derived from 12/15-LO KO mice). Mechanistic endpoints based on preliminary data will include mitochondrial dysfunction hepatocyte death (necrosis vs. apoptosis) ER stress and metabolism/ bioenergetics impacting steatosis/cell survival. The aims of this R03 build on my K01 research and extend that project. However here we are building on that foundation to leverage new questions in investigating the role of a specific fat type (and its oxidized metabolites) that is prevalent in the US. This focus s distinct and unique from my K01 research but will complement it very aptly. This proposal is consistent with the goals of NIDDK to investigate the causes/consequences of obesity.

project_terms:
Ablation;Acids;Acute;Air;Animal Model;Apoptosis;Arachidonate 15-Lipoxygenase;Attenuated;Bioenergetics;Carbohydrates;Cell Survival;Cells;Cessation of life;Chemicals;Clinical;Complement;Consumption;Data;Development;Diet;Dietary Fats;Disease;Dose;Environmental Exposure;Environmental Pollutants;Environmental Pollution;Enzymes;Exposure to;Fatty Liver;Fatty acid glycerol esters;Foundations;Genetic;Goals;Health;Hepatic;Hepatocyte;Hepatotoxicity;Human;Individual;Industrialization;Industry;Inflammation;Inflammatory Response;Injury;Knockout Mice;Linoleic Acids;Liver;Liver diseases;Metabolic;Metabolism;Molecular;National Institute of Diabetes and Digestive and Kidney Diseases;Necrosis;Non obese;Nutrient;Obesity;Occupational;Occupational Exposure;Organelles;Oxides;Pharmacology;Pilot Projects;Play;Polyunsaturated Fatty Acids;Predisposition;Production;Research;Risk;Risk Factors;Role;Solvents;Steatohepatitis;Stress;Tetrachloroethylene;Toxin;Trichloroethylene;United States;Up-Regulation;Vinyl Chloride;Water Supply;Work;base;contaminated drinking water;cytokine;drinking water;hepatotoxin;in vitro Model;in vivo;landfill;lipid metabolism;liver development;liver inflammation;liver injury;mitochondrial dysfunction;non-alcoholic fatty liver;octadecadienoic acid;oxidation;public health relevance;response;superfund site;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE   We propose that vinyl chloride exposure even below levels that are overtly hepatotoxic may increase the stimulated inflammatory response in the liver potentially adding another risk factor to the development of liver disease associated with diet induced obesity (i.e. non-alcoholic fattyliver disease). The project will focus on the interaction of vinyl chloride and specific dietary faty acids in experimental NAFLD.


application_id: 9202244
project_number: 1R56AI121281-01
administering_ic: NIAID
award_notice_date: 2016-02-08
opportunity_number: PAS-15-055
application_type: 1
activity_code: R56
ic: AI
serial_number: 121281
program_official: KEHN, PATRICIA J
project_start_date: 2016-02-15
project_end_date: 2018-01-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-02-15
project_title:
A novel immunomodulatory approach to overcome innate and adaptive immune barriers to islet transplantation

project_abstract:
DESCRIPTION (provided by applicant): Type I diabetes is a chronic autoimmune disease initiated and perpetuated by T cells responding to autoantigens expressed by insulin producing pancreatic beta cells. T1D affects 3 million children and adults in the US with healthcare costs exceeding $14.9 billion annually. Currently there is no cure for type 1 diabetes. Transplantation of allogeneic islets is a reliable method of achieving durable glucose homeostasis and preventing the devastating complications of type 1 diabetes. However there are four major barriers to allogeneic islet transplantation; i) ineffective engraftment ii) rejection iii) advere effects of immunosuppression used to control rejection and iv) shortage of cadaveric donor islets. Therefore there is a significant need for strategies that overcome these limitations of iset transplantation for a broader clinical practice. This R01 application is in response to NIH/NIAID "PAS-15-055" RFA and aims to develop an innovative and highly translational immunomodulatory protocol that overcomes these obstacles and achieves indefinite islet graft survival in the absence of chronic use of immunosuppression.  Infusion of islets into the liver viaportal vein the only route of transplantation in clinical use instantly exposes the graft to bloo and initiates an immediate blood-mediated inflammatory reaction (IBMIR). IBMIR is mediated by thrombotic and inflammatory reactions and is responsible for the destruction of 50-80% islets immediate post-transplantation. The remaining islets are then subject to rejection by the slower but potent adaptive immune responses. Significant early islet loss requires transplantation from 2-3 donors per recipients which further contribute to the shortage of cadaveric donors. The goal of this proposal is to develop powerful yet focused therapies to simultaneously target the immediate inflammatory reactions and adaptive immune response to prevent early and late graft loss. This will be accomplished by generating novel recombinant proteins with robust inhibitory functions on prothrombotic proinflammatory and adaptive immune reactions. These proteins will be engineered on pancreatic islets before transplantation for localized modulation of thrombotic and inflammatory responses to enhance engraftment and achieve indefinite graft survival without the chronic use of debilitating immunosuppression that is currently standard. This concept will be tested in three different allogeneic islet transplantation settings for efficay and mechanisms; chemically diabetic BALB/c-to-C57BL/6 mice spontaneously diabetic C57BL/6-to-NOD mice and human islets into humanized mice. These models will generate critical data relevant to the human setting. Furthermore proof-of-efficacy and the elucidation of the immune mechanisms regulating effective outcomes will expedite further refinement of this immunomodulatory concept and its eventual translation to nonhuman primates as a prelude to clinical trials for the treatment of type 1 diabetes.

project_terms:
Adult;Adverse effects;Affect;Allogenic;Apoptosis;Autoimmune Diseases;Biological Response Modifiers;Biotin;Blood;C57BL/6 Mouse;CD47 gene;Cessation of life;Child;Chronic;Clinical;Clinical Treatment;Clinical Trials;Coagulation Process;Complement;Data;Development;Diabetic mouse;Eating;Effector Cell;Engineering;Engraftment;Goals;Graft Rejection;Graft Survival;Health;Health Care Costs;Homologous Transplantation;Human;IL2RA gene;Immune;Immune response;Inbred BALB C Mice;Inbred NOD Mice;Infiltration;Inflammatory;Inflammatory Response;Infusion procedures;Insulin;Insulin-Dependent Diabetes Mellitus;Islets of Langerhans;Islets of Langerhans Transplantation;Lead;Leukocytes;Liver;Mediating;Membrane;Methods;Modeling;National Institute of Allergy and Infectious Disease;Natural immunosuppression;Outcome;Pancreas;Pathway interactions;Phagocytes;Phagocytosis;Pilot Projects;Platelet Activation;Play;Population;Portal vein structure;Prevention Protocols;Proteins;Prothrombin;Protocols documentation;Reaction;Recombinant Proteins;Regulatory T-Lymphocyte;Role;Route;SHPS-1 protein;Site;Stimulus;Streptavidin;Structure of beta Cell of islet;Surface;T-Lymphocyte;Technology;Testing;Therapeutic;Thrombin;Thrombomodulin;Thromboplastin;To autoantigen;Translations;Transplantation;United States National Institutes of Health;Work;adaptive immunity;allograft rejection;base;blood glucose regulation;cellular engineering;chronic autoimmune disease;clinical practice;combinatorial;design;diabetic;efficacy testing;humanized mouse;immunoregulation;innovation;islet;monocyte;mouse model;neutrophil;nonhuman primate;novel;novel strategies;prevent;response;standard care

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of population worldwide. Insulin as a standard treatment has major long-term complications; therefore the development of novel approaches to prevent and treat T1D is a significant therapeutic goal. The primary objective of this proposal is to develop an immunomodulatory protocol that prevents the rejection of pancreatic allogeneic islets for the treatment of T1D. If effective this approach will have immediate and important implications for the use of allogeneic islets for the treatment of T1D in humans.


application_id: 9201866
project_number: 2R44DC012741-02
project_title: Microfabricated Cochlear Electrode Array
administering_ic: NIDCD
award_notice_date: 2016-08-31
opportunity_number: PA-15-269
application_type: 2
activity_code: R44
ic: DC
serial_number: 012741
program_official: MILLER, ROGER
project_start_date: 2014-09-01
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-G (12)]
contact_pi_person_id: 11208190
contact_pi: JOHNSON, ANGELIQUE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 969965800
primary_uei: NPHRMGVU99E8
duns_number: 969965800
uei: NPHRMGVU99E8
fips: US
organization_id: 10030414
organization_name: MEMSTIM, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022654
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractCurrent cochlear implants while beneficial in their use are limited in their capabilities by hand-assembly of the electrode arrays. This tedious manufacturing method is very costly extremely labor-intensive and inadequate in implementing new technologies for improving speech recognition andmusic appreciation. A superior alternative to hand assembly is microfabrication which is a fullyautomated low cost and high yield manufacturing process that is capable of implementing a varietyof innovations including smaller array size for residual hearing preservation drug delivery channelsfor inner ear health and cell regeneration and strain gauges for improved performance duringsurgical insertion. Microfabrication is a very promising alternative to hand-assembly but has yet tomeet the following requirements for commercialization: (1) substrates must be composed of provenlong-term implantable materials (USP class VI) (2) electrode arrays must be compatible withstandard surgical insertion techniques (3) substrate and electrode sites must be able to withstandlong-term electrical stimulation in the body (4) the array must be long enough to extend from the tipof the cochlea to the location behind the ear where the electronics are implanted under the skin and(5) the array must have electrical wiring that is compatible with the electrical feedthrough pins of theimplantable cochlear stimulator (ICS).During Phase I MEMStim showed that it is feasible to produce a microfabricated cochlear electrodearray out of medical grade materials that can meet the commercial requirements (1)  (3). The goal ofPhase II will be to produce just such an array as a minimum viable product (MVP) for cochlearimplant manufacturers. The MVP will address requirements (4)  (5) and further improve upon thePhase I results of requirement (2). In order to accomplish the Phase II goal the following SpecificAims will be accomplished: (Aim 1) produce a full length microfabricated cochlear array with anintegrated cable that can be bonded to an implantable cochlear stimulator and complies withelectrical mechanical durability biocompatibility and FDA safety requirements specified incommunications with cochlear implant manufacturers and (Aim 2) produce a connector scheme forintegrating a microfabricated cochlear electrode to the feedthroughs of an implantable cochlearstimulator. The expected outcome is an array that can be integrated by customers into their cochlearimplant systems and pass all handling/use/safety tests that cochlear implant manufacturers wouldneed to seek approval from the FDA.

project_terms:
Address;Adopted;Adult;Basilar Membrane;Biological Preservation;Cells;Clinical Trials;Cochlear Implants;Cochlear structure;Communication;Corrosion;Deposition;Drops;Drug Delivery Systems;Ear structure;Electric Stimulation;Electric Wiring;Electrodes;Electronics;Environment;Fracture;Goals;Hand;Health;Hearing;Hearing Aids;Hearing Impaired Persons;Human;Implant;Labyrinth;Learning;Length;Ligaments;Location;Manufacturer Name;Mechanics;Medical;Methods;Microfabrication;Music;Natural regeneration;Operative Surgical Procedures;Otolaryngology;Outcome;Performance;Pharmaceutical Preparations;Phase;Physiologic pulse;Positioning Attribute;Prevention;Process;Research;Residual state;Safety;Saline;Scheme;Shapes;Site;Skin;Specific qualifier value;Speech;Spiral Lamina;System;Techniques;Technology;Temporal bone structure;Testing;Time;Toxicity Tests;Work;abstracting;biomaterial compatibility;commercialization;cost;cytotoxicity;hearing impairment;improved;innovation;manufacturing process;meetings;millimeter;nanometer;new technology;novel;prototype;safety testing;speech recognition;success;systemic toxicity;technological innovation;visual feedback

public_health_relevance:
Project NarrativeCochlear implants allow the profoundly deaf to achieve reasonable word recognition inquiet environments but technological innovations to achieve fuller appreciation of musicand speech are severely limited by the shortcomings of current hand assemblymanufacturing methods for cochlear electrode arrays. MEMStim LLC will develop asuperior alternative to hand-assembly microfabrication. This novel method is a fullyautomated low cost and high yield manufacturing process capable of implementingtechnological innovations that will provide benefits such as small electrode array size forresidual hearing prevention drug delivery channels for inner ear health and cellregeneration and strain gauges for improved surgical safety outcomes.


application_id: 9201588
project_number: 7R21OD018297-02
project_title: Restoring Respiratory Motor function with Cell Therapy after Cervical Spinal Cord Injury
administering_ic: OD
award_notice_date: 2016-03-31
opportunity_number: PA-14-078
application_type: 7
activity_code: R21
ic: OD
serial_number: 018297
program_official: MIROCHNITCHENKO, OLEG
project_start_date: 2015-04-01
project_end_date: 2018-09-30
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 8838438
contact_pi: ALILAIN, WARREN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): More than half of all spinal cord injuries (SCI) occur at the cervical level. At this level are the components of the central nervous system mediating respiratory motor activity including the phrenic motor neurons which innervate the diaphragm and the bulbospinal tracts that provide the inspiratory drive to these cells. Therefore injuries a this level can result in diaphragmatic paralysis and the inability to breathe. In order to survivemechanical ventilation is needed for these patients severely limiting their quality of life. In ths grant application we plan to utilize our newly developed cervical contusion injury model. This cervical contusion injury model is significantly improved compared to previous models of cervical injury in that accompanying it are severe respiratory motor deficits in a clinically relevnt setting. Additionally with this model we can assay potential therapeutic interventions and their effect on repairing strengthening and/or promoting the plasticity of pathways damaged by SCI. Among these interventions is stem cell therapy. Previous work has demonstrated the effectiveness of multipotent adult progenitor cell (MAPC) therapy in restoring locomotor and bladder function in thoracic SCI models. We now propose to determine the effectiveness of MAPC treatment in rescuing the diaphragm from paralysis. If this cell therapy is indeed therapeutically beneficial there would be a significant and positive impact for a major portion ofthe SCI population.

project_terms:
Adult;Americas;Animal Model;Animals;Applications Grants;Biological Assay;Bladder;Breathing;Caring;Cell Therapy;Cells;Cervical;Cervical spinal cord injury;Chest;Communities;Contralateral;Contusions;Development;Effectiveness;Emotional;Ethics;FDA approved;Facilities and Administrative Costs;Family member;Funding Opportunities;Goals;Health;Injury;Intervention;Knowledge;Laboratories;Lateral;Limb structure;Mechanical Ventilators;Mechanical ventilation;Mediating;Medical;Modeling;Motor;Motor Activity;Motor Neurons;Natural regeneration;Neuraxis;Paralysed;Pathway interactions;Patient Care;Patients;Population;Process;Publications;Quality of life;Recovery;Respiratory Diaphragm;Respiratory Paralysis;Side;Spinal Cord;Spinal cord damage;Spinal cord injury;Spinal cord injury patients;Stem cells;Testing;Therapeutic;Therapeutic Intervention;Thoracic spinal cord structure;Time;Tissues;United States;Whole Body Plethysmography;Work;base;care burden;clinically relevant;cost;functional outcomes;improved;injured;male;mortality;motor deficit;motor recovery;neurophysiology;repaired;research study;respiratory;stem cell therapy;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Around 300000 people in the United State of America currently have a spinal cord injury with at least 12000 new cases each year. Many of those injured are adult young males. In addition to the emotional costs and high burden of care for family members monetary expenses can and often exceed millions of dollars. Specifically direct medical costs associated with treating SCI patients is estimated at over $40 billion annually with indirect costs for care of these patients at a staggering $300 billion annually. Currently there is no FDA approved cure for paralysis. This grant proposal seeks to investigate potential cures to restore respiratory motor function after one of the most common types of SCI (cervical spinal cord damage) and thereby relieve the costs of care and improve the quality of life of a significant portion of the SCI community.


application_id: 9201446
project_number: 1R43OH011239-01
project_title: Computerized system for predicting noise emission from mining machines
administering_ic: NIOSH
award_notice_date: 2016-08-24
opportunity_number: PA-15-269
application_type: 1
activity_code: R43
ic: OH
serial_number: 011239
program_official: DEARWENT, STEVE
project_start_date: 2016-09-01
project_end_date: 2017-02-28
study_section: Special Emphasis Panel[ZRG1 IMST-K (14)]
contact_pi_person_id: 10760401
contact_pi: STENCEL, JOHN MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 038094228
primary_uei: UFCJJCJ8KKJ3
duns_number: 038094228
uei: UFCJJCJ8KKJ3
fips: US
organization_id: 10040786
organization_name: TRIBO FLOW SEPARATIONS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405098542
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The control or mitigation of equipment noise is paramount for worker protection in mines.If a computerized system was developed that accurately predicted noise emission duringequipment design and siting the current need to build site and then operate equipment tounderstand or control its noise emission would be eliminated. This project aims to develop sucha computerized system. With success it would improve timelines for developing andimplementing worker protection devices and protocols; decrease substantially the amount oftime and costs associated with noise emission measurements and control practices; providegreater worker safety in all industrial activities; and lead to the use of predictive noise analysesfor equipment that is to be used in all industrial residential and commercial buildings. The goals of the project are to: develop techniques and algorithms for predicting noisesound pressure from mining equipment during the design and siting process; and show thefeasibility of a computerized system for predicting worker noise exposure from miningequipment noise emissions. These goals are attained through comprehensive noise emissiontests and simulations that include cooperative research between Tribo Flow Separations andthe University of Kentucky and interactions with personnel and assessments of miningequipment at the Pittsburgh Office of Mine Safety and Health Research. The long-term objectives include: establishing the scientific basis for reliable boundaryelement method and sub-structured boundary element method simulations for determiningnoise transfer functions; refining the applicability of patch contribution analysis on scale modelsof equipment and on operating equipment; developing reliable specifications for computeralgorithms useful for defining noise emission during equipment design and siting; and initiateinteractions with a mining equipment manufacturer to prepare for demonstration andcommercialization of the computerized system. With success in the research it is expected that predictions of worker noise exposurebefore machinery is placed in operation will be possible thereby enabling noise mitigationprocedures and noise protection protocols to be put into effect before a machine is turned on.This computerized system will promote worker safety while decreasing the extent of workerinjuries and illnesses caused by vibration and noise.

public_health_relevance:
The research focuses on developing a computerized system which can predict noise levels fromlarge machinery during design and planned siting within mining operations. With successpredictions could be made of worker noise exposure before machinery is placed in operationthereby enabling noise mitigation procedures and noise protection protocols to be put into effectbefore a machine is turned on. This system will promote worker safety while decreasing theextent of worker injuries and illnesses caused by vibration and noise.


application_id: 9200082
project_number: 1R41AG053115-01A1
project_title: Target Identification for Novel Small Molecule Therapeutic for Alzheimer's disease
administering_ic: NIA
award_notice_date: 2016-09-15
opportunity_number: PA-15-270
application_type: 1
activity_code: R41
ic: AG
serial_number: 053115
suffix: A1
program_official: REFOLO, LORENZO
project_start_date: 2016-09-15
project_end_date: 2017-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-M (11)]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 841834083
primary_uei: JK7PN2MFXEU2
duns_number: 841834083
uei: JK7PN2MFXEU2
fips: US
organization_id: 10022006
organization_name: COPLEX THERAPEUTICS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
project_abstract:
ABSTRACTTraditional approaches to drug development for Alzheimers disease are becoming increasinglyexpensive and in many cases disappointingly unsuccessful. Based on preliminary in vitro and invivo studies we have identified a novel small molecule (methyl 24-dimethyl-5-oxo-56-dihydrobenzo[c][27]naphthyridine-1-carboxylate; (UK-101)) that significantly decreases A1-42production and pro-inflammatory (M1) cytokines while simultaneously inducing anti-inflammatory (M2a) cytokines. Although our preliminary data show UK-101 effectively modifies2 critical neuropathologic features of AD with no apparent adverse effects the drug targetremains unclear. Based on preliminary in silico modeling and in vitro data that suggest UK-101may modulate mGluR5 an allosteric glutamate receptor recently identified as a potentialtherapeutic target in AD the aims of the current proposal are to verify that mGluR5 is the drugtarget of UK-101 to quantify the binding constant of UK-101 and to verify that there are nosignificant off target effects of the drug. If successful the data obtained in this proposal willallow further structure activity studies and most importantly establish a specific target for UK-101.

project_terms:
Abeta clearance;Abeta synthesis;Adverse effects;Affinity;Age;Alzheimer's Disease;Amyloid beta-Protein;Amyloid deposition;Anti-Inflammatory Agents;Anti-inflammatory;Binding;Cerebellum;Cerebral cortex;Chemical Structure;Clinical;Clinical Trials;Computer Simulation;Data;Diet;Disease Progression;Docking;Drug Targeting;Evaluation;Formic Acids;Future;Glutamate Receptor;Immunoassay;Immunotherapy;In Vitro;Industry;Inflammatory;Interleukin-1 beta;Investigational Therapies;Label;Legal patent;Lipopolysaccharides;Measures;Mediating;Membrane;Modeling;Mono-S;Mus;Naphthyridines;National Institute of Mental Health;Orphan;Outcome;Pathology;Patients;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Plague;Preclinical Drug Evaluation;Process;Production;Protein Region;Proteins;Psychotropic Drugs;Rattus;Research;Risk;Series;Services;Signal Transduction;Specificity;Structure;Structure of choroid plexus;Structure-Activity Relationship;TNF gene;Testing;Therapeutic;Therapeutic Studies;Toxic effect;Tritium;base;beta-site APP cleaving enzyme 1;carboxylate;commercialization;cytokine;drug development;drug structure;familial Alzheimer disease;gamma secretase;in vitro Model;in vivo;inhibitor/antagonist;metabotropic glutamate receptor 5;mouse model;neuroinflammation;novel;novel therapeutics;overexpression;programs;protective effect;pyridine;receptor coupling;research study;response;screening;small molecule;small molecule therapeutics;tau Proteins;therapeutic target

public_health_relevance:
NarrativeAlthough current therapeutics for Alzheimers disease (AD) show clinical benefit in some patients manydo not respond. Additionally current drugs do not significantly modify disease progression. For thesereasons there is a critical need to identify additional therapeutics that can be initiated early in thedisease progression to alter progression of the disease. Preliminary and future studies described inthis proposal aim to define the pharmacologic target of a novel small molecule (methyl 24-dimethyl-5-oxo-56-dihydrobenzo[c][27]naphthyridine-1-carboxylate; (UK-101) that shows significant protectionagainst neuroinflammation and amyloid beta peptide processing in well-established mouse models ofAD pathology.


application_id: 9199545
project_number: 2R44EY021940-02A1
project_title: Implantable Optical Intraocular Pressure Sensor for Improved Glaucoma Treatment
administering_ic: NEI
award_notice_date: 2016-08-31
opportunity_number: PA-15-269
application_type: 2
activity_code: R44
ic: EY
serial_number: 021940
suffix: A1
program_official: WUJEK, JEROME R
project_start_date: 2012-04-01
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZRG1 ETTN-G (12)]
contact_pi_person_id: 8625040
contact_pi: HASTINGS, JEFFREY TODD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 964829142
primary_uei: ZJUUV8RMN287
duns_number: 964829142
uei: ZJUUV8RMN287
fips: US
organization_id: 10027679
organization_name: BROCKMAN-HASTINGS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACTBrockman-Hastings LLC seeks to reduce vision loss for glaucoma sufferers by creating a simpleaccurate and clinically acceptable system for monitoring intraocular pressure (IOP). Trends indicatethat by 2020 approximately 80 million people worldwide will have glaucoma 11 million of whom willbecome blind. Elevated IOP remains the key risk factor and treated symptom for glaucoma andophthalmologists routinely measure IOP during office visits. However infrequent single pointmeasurements are often insufficient to fully manage glaucoma and infrequent measurements make itdifficult to assess the effectiveness of pharmaceutical or surgical treatments. To address this problemseveral research groups have developed implantable intraocular pressure sensors; however thesedevices have thus far proven too large complex inaccurate and/or high risk for rapid clinical adoption.In contrast Brockman-Hastings sensor does not include any implanted microelectronic circuitry orexternal or internal power sources. Instead the system relies on the reflection of light from the sensorsactive region (smaller than one square millimeter) and a hand held or eye-glass-mounted readout unitcaptures an infrared image to measure IOP. The simplicity of our sensor minimizes its physical sizeproviding for an aesthetic implant and allowing a simple lower-risk implantation procedure.In Phase I we established feasibility of the technology by achieving both specific aims: (1) sub-1 mmHgsensing accuracy in a simulated physiological environment and (2) sub 2-mmHg precision and onemonth tolerability in the rabbit eye. Our phase II hypothesis is that the optical IOP monitoring systembased around a refined anterior chamber implant will provide measurements sufficiently accurate forglaucoma management and will satisfy preclinical requirements for an investigational device exemption.To establish this we propose two specific aims: (1) Demonstrate that the optical IOP monitoring systemmeets preclinical performance requirements (1 mmHg accuracy) under real-time accelerated agingand in-vivo (rabbit eye) conditions and (2) Demonstrate that the optical IOP monitoring system satisfiespreclinical (mechanical dimensional biocompatibility and sterility) safety requirements. Successfulcommercialization of this device could ultimately benefit millions of glaucoma patients especially thosethat could immediately combine the sensor implantation with another eye surgery. Even this narrowermarket encompasses ~100000 glaucoma patients per year in the U.S. alone. Ultimately the systemwill reduce the human and financial cost of glaucoma-related vision loss by providing physicians withaccurate long-term IOP data on which to base treatment decisions and assess treatment effectiveness.

project_terms:
5 year old;Address;Adoption;Aging;Algorithms;Biocompatible Materials;Blindness;Cataract Extraction;Clinical;Clinical Trials;Complex;Compliance behavior;Data;Devices;Diagnosis;Effectiveness;Electronics;Elements;Ensure;Environment;Esthetics;Event;Eye;Failure;Feedback;Financial cost;Glass;Glaucoma;Goals;Hand;Health;Human;Image;Implant;Implantation procedure;In Vitro;Intraocular lens implant device;Investments;Knowledge;Lasers;Light;Marketing;Measurement;Measures;Mechanics;Monitor;Office Visits;Operative Surgical Procedures;Ophthalmologic Surgical Procedures;Ophthalmologist;Optics;Oryctolagus cuniculus;Outcome;Patients;Performance;Pharmacologic Substance;Phase;Physicians;Physiologic Intraocular Pressure;Physiological;Power Sources;Preclinical Testing;Recovery;Research;Research Design;Risk;Risk Factors;Safety;Small Business Innovation Research Grant;Software Design;Specialist;Sterility;System;Systems Analysis;Technology;Testing;Third-Party Payer;Time;Treatment Effectiveness;Visual;Visual impairment;anterior chamber;base;biomaterial compatibility;blind;clinically relevant;commercial application;commercialization;cost;experience;high intraocular pressure;high risk;image processing;implantation;implanted sensor;improved;in vivo;meetings;millimeter;optical sensor;performance tests;pre-clinical;preclinical safety;prototype;sensor;success;symptom treatment;trend

public_health_relevance:
PUBLIC HEALTH RELEVANCETrends indicate that by 2020 there will be 80 million people worldwide with glaucoma 11 million ofwhom will become blind. Vision loss could be reduced if more frequent and longer term intraocularpressure monitoring were available to glaucoma patients and their physicians. In this SBIR Phase IIeffort Brockman-Hastings LLC will demonstrate the performance and safety of an intraocular pressuremonitoring system based on a simple implantable optical sensor.


application_id: 9198792
project_number: 5R01NS091146-03
project_title: Anti-Oxidant Promoting Cytokine LIF Enhances Neural Cell Survival During Ischemia
administering_ic: NINDS
award_notice_date: 2016-12-09
opportunity_number: PA-14-078
application_type: 5
activity_code: R01
ic: NS
serial_number: 091146
program_official: BOSETTI, FRANCESCA
project_start_date: 2016-05-01
project_end_date: 2019-12-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 1879898
contact_pi: PENNYPACKER, KEITH R
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Age;Anatomy;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Behavioral;Binding;Cell Survival;Cells;Clinic;Clinical;Data;Dose;Elderly;Electrophoretic Mobility Shift Assay;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;FDA approved;Female;Gene Expression;Histologic;Human;Immunohistochemistry;Infarction;Intravenous;Ischemia;Knockout Mice;LIF gene;Laboratories;Measures;Middle Cerebral Artery Occlusion;Modeling;Motor Skills;Neurologic;Neurons;Occlusion injury;Oligodendroglia;Performance;Protein Isoforms;Protein Kinase;Proteins;Public Health;Rattus;Records;Recovery;Recovery of Function;Regimen;Rodent;Safety;Signal Transduction;Small Interfering RNA;Superoxide Dismutase;Techniques;Therapeutic;Translating;Treatment Factor;Treatment Protocols;activating transcription factor;base;combat;cytokine;enhancing factor;experimental study;functional outcomes;gray matter;improved;individualized medicine;interest;knock-down;male;pre-clinical;promoter;public health relevance;response;sex;stroke;transcription factor;treatment strategy;white matter


application_id: 9198697
project_number: 7R21CA184573-02
project_title: A novel multi-targeted therapy for breast cancer resistance
administering_ic: NCI
award_notice_date: 2016-02-02
opportunity_number: PA-14-078
application_type: 7
activity_code: R21
ic: CA
serial_number: 184573
program_official: YOVANDICH, JASON L
project_start_date: 2016-02-01
project_end_date: 2017-06-30
study_section: ZCA1-RTRB-E(M1)
contact_pi_person_id: 7799129
contact_pi: BROUXHON, SABINE M
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Over the last decade the most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against growth factor receptors including the human epidermal growth factor receptors (HER1 and HER2) and drugs for hormone-receptor-positive disease. However despite such encouraging results patients that are initially responsive to these drugs eventually become resistant within one year of therapy. Multiple mechanisms responsible for resistance have been proposed including compensatory crosstalk with alternate receptor tyrosine kinases (i.e. HER1-4 IGF-1R) hyper-activation of downstream MAPK-PI3K/Akt/mTOR signaling activation of the inhibitor of apoptotic proteins (IAPs) and inactivation of PTEN and p53.  We have identified soluble E-cadherin (sEcad) as a novel therapeutic target and have developed monoclonal antibodies targeting sEcad as an innovative therapy that directly kills cancer cells spares normal cells and overcomes these host resistance pathways. Therefore in this grant application we propose to first narrow down which HER or non-HER receptors (or combinations) are involved in the efficacy of our antibody- based therapy. We then will test whether combinatorial strategies involving HER or non-HER inhibitors that act via different mechanism(s) of action than our antibody may act additively or synergistically to suppress tumor growth and dissect some of the mechanism(s) involved. Lastly we propose to complement our antibody with a panel of PD markers so as to ensure that the antibody is exerting its intended biologic outcome and perform preliminary studies to confirm no off-target effects. Altogether we believe that our innovative therapy will make substantial strides in cure rates and in progression-free survival of patients with HER and non-HER-positive breast cancers that progress beyond targeted or other conventional therapies.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against the human epidermal growth factor receptors (HER1 and HER2) and therapies for hormone- receptor-positive disease. However despite an initial positive response to these therapies the majority of patient's exhibit resistance - rendering the therapy ineffective within one year of treatment. Thisproject will test an innovative antibody-based therapy that successfully inhibits many of these resistance pathways and kills resistant cells - without exhibiting any untoward cytotoxicity to normal cells.


application_id: 9198550
project_number: 5R01ES016893-10
project_title: Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
administering_ic: NIEHS
award_notice_date: 2016-12-22
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: ES
serial_number: 016893
program_official: TYSON, FREDERICK L
project_start_date: 2009-07-06
project_end_date: 2018-12-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Hexavalent chromium (Cr(VI)) also known as chromate is a major public health concern. Chromates particularly the insoluble compounds are well-established human lung carcinogens. Our study focuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis which are currently unknown. Recent studies indicate that particulate Cr(VI) induces chromosome instability which is a hallmark of human lung tumors. However how Cr(VI) induces chromosome instability is poorly understood. Our preliminary data show that chronic exposure to particulate Cr(VI) induces a DNA repair deficient phenotype that underlies the chromosome instability and thus the goal of this research is to characterize this repair deficiency and its impact and understand the mechanisms that cause it to occur. We will test the hypothesis that particulate Cr(VI) induces epigenetic changes inactivating homologous recombination repair of Cr(VI)-induced DNA double strand breaks resulting in increased chromosome instability and carcinogenesis. We will test this hypothesis through four interrelated specific aims. Aim 1 will characterize the homologous recombination repair defect and show that particulate Cr(VI) causes cells to inactivate Rad51-mediated response and switch to lower fidelity non-homologous end joining (NHEJ) repair using immunoblotting immunofluorescence and repair assays. Aim 2 will show that the cells with particulate Cr(VI)-inactivated Rad51 response acquire chromosome instability and undergo neoplastic transformation using cytogenetic techniques and assays for contact- uninhibited and anchorage independent growth. Aim 3 will identify an epigenetic change (increased acetylation) that causes the loss of Rad51 response by affecting E2F1 ATM Rad51C and Rad51 with assays for acetylation status gene expression and protein interactions and localization. FinallyAim 4 will characterize the mechanism for particulate Cr(VI)-induced acetylation changes studying Cr(VI) binding to acetyl groups using assays for acetylation and histone deacetylase activity. Each aim will focus on human lung cells and confirm key findings in human Cr(VI) tumors. Results will lead to the first reports of detailed information of the interactions of Cr(VI with DNA double strand break machinery acetylation status and the first characterizations of these aspects in tumors from Cr(VI)-exposed workers. This research is significant because it will provide: 1) An understanding of particulate Cr(VI)'s carcinogenic mechanism; 2) Essential information to better assess the risk of exposure to particulates; and 3) A mechanistic approach for further study of Cr(VI) other metals and lung cancer in general.

project_terms:
Acetylation;Affect;Anchorage-Independent Growth;Binding;Biological Assay;Cancer Etiology;Carcinogen exposure;Carcinogens;Cells;Chromates;Chromosomal Instability;Chronic;Cytogenetic Analysis;Cytoplasm;DNA Double Strand Break;DNA Repair;Data;Defect;E2F1 gene;Environmental and Occupational Exposure;Epigenetic Process;Epithelial Cells;Event;Exposure to;Fibroblasts;Frequencies;G-Banding;Gene Expression;Genomic Instability;Goals;Histone Deacetylase;Histone Deacetylation;Human;Immunoblotting;Immunofluorescence Immunologic;In Vitro;Ions;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Mediating;Metals;Modeling;Molecular;Mutation;Neoplastic Cell Transformation;Nonhomologous DNA End Joining;Nuclear;Particulate;Peptide Mapping;Phenotype;Proteins;Public Health;Publishing;Reporting;Research;Risk;Salts;Solubility;Spectral Karyotyping;System;Techniques;Testing;Toxicology;Zinc;carcinogenesis;carcinogenicity;chromium hexavalent ion;homologous recombination;interest;prevent;public health relevance;recombinational repair;repaired;response;tandem mass spectrometry;tumor;zinc chromate

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Hexavalent chromium (Cr(VI)) is a human lung carcinogen with widespread occupational and environmental exposure. How Cr(VI) causes human cancer is unknown. Our study advances our basic understanding of the cellular and molecular mechanisms underlying how Cr(VI) causes cancer and informs us about how cells protect against Cr(VI)-induced genomic instability. Our findings will help us identify new potential treatment targets and approaches to reduce or prevent Cr(VI)-induced lung cancer and to better assess the risk of exposure to this major public health concern. Finally we will have established a mechanistic model in a human lung cell system that will allow us to conduct studies for other factors important for preventing human lung cancer both generally and by Cr(VI) and other agents.


application_id: 9198017
project_number: 5R01GM070559-11
project_title: Epigenetic and post-translational modifier regulation of juvenile hormone action
administering_ic: NIGMS
award_notice_date: 2017-01-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 070559
program_official: AINSZTEIN, ALEXANDRA M
project_start_date: 2005-02-01
project_end_date: 2020-01-31
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There has been a continuous demand for the development of insect control methods that are target-specific. Juvenile hormone (JH) and ecdysteroids are the major hormones that regulate development and reproduction in insects. Since these hormones are not present in vertebrates they represent attractive targets for the development of insect control methods. Hindering this effort is the lack of understanding on the molecular basis of JH action. Tremendous progress has been made in understanding JH action at the molecular level during the past few years. A bHLH transcription factor methoprene tolerant (Met) has been identified as a JH receptor. A steroid receptor co-activator homologue (SRC/Taiman/FISC) and Cycle have been identified as important co-factors involved in JH action. Kruppel homologue (Kr-h1) and bHLH transcription factor Hairy and E93 have been identified as important transcription factors that mediate JH action. Preliminary experiments showed that Cyclic AMP response-element binding protein (CBP) is required for acetylation of histone H3 as well as for JH induction of JH-response genes in Tribolium castaneum tissues TcA and Aag-2 cells. In addition histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) also induces expression of JH-response genes in TcA and Aag-2 cells. Chromatin modifiers Brahma Snr1 and CHD1 but not DNA methyl transferase are required for regulation of metamorphosis and reproduction in T. castaneum. JH exerts diverse functions in different tissues and under various physiological conditions. We hypothesize that epigenetic and post- translational modification of proteins involved in JH action play critical roles in multi-dimensionl gene regulation strategies employed by JH. Therefore the main objective of this proposal is to capitalize on these latest developments to identify epigenetic modifiers and determine their mechanisms of action in modulation of JH response using T. castaneum TcA and Aag-2 cells. The two Specific Aims of the proposal are 1. To identify key players involved in epigenetic and post-translational modifier regulation of JH action and 2. To determine the mechanisms involved in epigenetic and post-translational modifier regulation of JH action. In the first Specific Aim w will employ RNAi cell culture and reporter assays to identify and characterize key proteins including histone acetyl transferases (HAT) HDACs and chromatic modifiers involved in modulation of JH action. Temporal spatial and hormonal regulation of identified genes as well as their function in JH action will be determined. In the second Specific Aim we will employ mass spectrometry RNAi two-hybrid pull- down Chip and reporter assays to identify acetylated lysines in Met domains of HATs HDACs and Brahma Snr1 and CHD1 required for JH action localize HATs HDACs and Brahma Snr1 and CHD1 on Kr-h1 Hairy and E93 promoters and identify interacting partners of HATs HDACs Brahma Snr1 and CHD1. The expected outcome of this study an understanding of the molecular basis of JH action and identification of critical proteins involved in JH action will help in development of methods for control of insect vectors. The proposed studies will also advance our knowledge on epigenetic and post-translational modification of histones and other nuclear proteins especially on the functions and mechanisms of action of the modifiers.

project_terms:
Acetylation;Adult;Agonist;Biological;Biological Assay;Biological Metamorphosis;Biological Models;CHD1 gene;Cell Culture Techniques;Cells;Chromatin;Culicidae;Cyclic AMP-Responsive DNA-Binding Protein;Development;Disease;Disease Vectors;Ecdysone;Ecdysteroids;Ensure;Epigenetic Process;Event;Food;Gene Expression Regulation;Genes;Helix-Turn-Helix Motifs;Histone Acetylation;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Histones;Homologous Gene;Hormone Receptor;Hormones;Human;Insect Control;Insect Vectors;Insecta;Insecticides;Juvenile Hormones;Knowledge;Laboratories;Livestock;Lysine;Mass Spectrum Analysis;Mediating;Medicine;Methods;Methoprene;Molecular;Molting;Nuclear Proteins;Outcome Study;Physiological;Play;Post-Translational Protein Processing;Post-Translational Regulation;Proteins;RNA Interference;Regulation;Reporter;Reproduction;Research;Role;Steroid Receptors;Testing;Tissues;Transferase;Tribolium;Trichostatin A;Vertebrates;base;brahma;experimental study;genome sequencing;histone modification;hormone regulation;human disease;method development;novel;promoter;public health relevance;receptor;response;success;transcription factor;vector control;whole genome;yeast two hybrid system

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Mosquitoes transmit deadly diseases. The research proposed in this application will provide information of potential importance for development of insecticide for vector control. The proposed studies will reveal functions and mechanisms of action of epigenetic marks which will help in understanding epigenetics of human diseases.


application_id: 9197940
project_number: 5R01AI051517-13
project_title: Paramyxovirus F protein mediated membrane fusion
administering_ic: NIAID
award_notice_date: 2016-12-21
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 051517
program_official: PARK, EUN-CHUNG
project_start_date: 2002-05-15
project_end_date: 2019-12-31
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Compelling work in the last decade has shown that transmembrane domains (TMDs) once thought to function solely as hydrophobic anchors are central players driving cellular protein oligomerization cell signaling and regulation of channelfunction. However the role of TMDs in viral glycoprotein stability and function remains poorly understood. During the previous funding period our studies of the Hendra virus (HeV) fusion (F) protein identified key roles for TMDs in regulation of F protein stability cellular trafficking ad fusion function. Our novel studies utilizing sedimentation equilibrium (SE) analysis established that F protein TMDs efficiently trimerize separate from the rest of the protein. Altered TM-TM association was found for multiple functionally important mutations implicating TM-TM interactions in regulation of F protein folding and function. The long-term goal of our research isto understand the molecular details and regulation of membrane fusion promoted by the paramyxovirus F proteins. The overall hypothesis of this proposal is that interactions of the TMD with itself and the lipid environment are critical for fusion protein stability and function makin these interactions potential targets for antiviral therapeutics. To test this important hypothesiswe will pursue three specific aims. First we will define key elements driving F protein TM-TM interactions including defining the role of a L/I heptad in TM-TM association and Hendra F protein stability. Second we will determine how the TMD affects fusion triggering and promotion of membrane fusion with a focus on the role of C-terminal -branched residues and a determination of the conformational changes that can occur when TM-TM interactions cannot be released. Third we will dissect the role of the lipid environment in prefusion F stability in the context of cellular and viral membranes. These important experiments will provide critical new insight into the role of TMDs in regulation of F protein stability and fusion promotion.

project_terms:
Address;Affect;Antiviral Agents;Automobile Driving;C-terminal;Ca(2+)-Transporting ATPase;Cells;Characteristics;Chimeric Proteins;Cholesterol;Cytoplasmic Tail;Data;Development;Dissociation;Elements;Environment;Family;Funding;Glycoproteins;Goals;Hendra Virus;Human;Human Metapneumovirus;Hydrophobicity;Individual;Infection;Kinetics;Lipids;Measles;Mediating;Membrane;Membrane Fusion;Membrane Fusion Activity;Membrane Lipids;Molecular;Molecular Conformation;Mutation;Neuropilins;Paramyxoviridae;Paramyxovirus;Paramyxovirus Fusion Protein;Peptides;Process;Proteins;Regulation;Research;Respiratory syncytial virus;Rest;Role;Sarcoplasmic Reticulum;Signal Transduction;Sphingolipids;Structure;System;Testing;Therapeutic;Time;Transmembrane Domain;Vaccines;Viral;Viral Fusion Proteins;Viral Proteins;Virus;Virus-like particle;Work;Zoonoses;disulfide bond;experimental study;insight;mutant;novel;particle;pathogen;prevent;protein folding;protein function;public health relevance;sedimentation equilibrium;trafficking;virus envelope

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Viral fusion proteins promote fusion between the viral membrane and a membrane of the target cell a critical first step in the infection of enveloped viruses. Studies to determine factors regulating the stability and function of these proteins are important to the development of novel antiviral approaches targeting these viral proteins. This proposal addresses the role of the paramyxovirus fusion protein transmembrane domain is control of fusion protein stability and membrane fusion activity potentially identifying a novel target for antivirals.


application_id: 9197935
project_number: 5R21AG050146-02
project_title: Testing a therapeutic strategy for hippocampal sclerosis of aging a key AD mimic
administering_ic: NIA
award_notice_date: 2016-12-21
opportunity_number: PAR-13-049
application_type: 5
activity_code: R21
ic: AG
serial_number: 050146
program_official: WISE, BRADLEY C
project_start_date: 2016-01-01
project_end_date: 2017-11-30
study_section: Drug Discovery for the Nervous System Study Section[DDNS]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Diseases that mimic Alzheimer's disease (AD) are understudied causes of cognitive impairment in the elderly. Poor understanding of these diseases has hampered AD clinical trials while leaving important illnesses largely unaddressed from a clinical research perspective. A common and high-morbidity "AD mimic" is hippocampal sclerosis of aging (HS-Aging). HS-Aging is characterized by cell loss and astrocytosis in the hippocampus with phosphorylated TDP-43 (P-TDP-43) pathology not correlated with AD-type pathology nor with APOE genotype. HS-Aging affects 10-25% of persons above age 85 years. The PI of the current proposal has studied HS-Aging extensively including the first HS-Aging genome-wide association study (GWAS). A genetic polymorphism in the ABCC9 gene is linked to HS-Aging pathology. Importantly we recently (Jan 2015) published a paper that replicated this observation in a separate group of research volunteers. The ABCC9 mutation enables us to address a central as-yet unrealized promise of genomics studies: clinical relevance. Remarkably the GWAS-identified HS-Aging risk gene ABCC9 is a "druggable target"-both agonist and antagonist drugs are used widely in humans. In a prior published study we found that exposure to sulfonylureas (oral anti-diabetic drugs that antagonize ABCC9 protein function) is associated with increased risk for HS-Aging pathology in humans controlling for other factors. We need to assess the potential to target ABCC9 in a preclinical model for more rigorous control of experimental parameters. That will enable us to test the impact of an ABCC9 agonist drug with the opposite effects of sulfonylureas as a potential therapy for clinical HS-Aging. Overall Hypothesis: Pharmacologic ABCC9 regulation provides a therapeutic strategy for HS-Aging. We propose proof-of-concept preclinical studies to test the specific hypothesis that ABCC9 agonist nicorandil attenuates pathologic and behavioral features of HS-Aging in a mouse model. Specific Aims: 1. Characterize the first preclinical model of HS-Aging. In GRN knockout (GRN-KO) mice our studies indicate the presence of brain changes that model features of human HS-Aging including hippocampal P-TDP-43 pathology and hippocampus-related neurobehavioral deficits. 2. Based on studies in humans test in the GRN-KO mouse model the hypothesis that a sulfonylurea drug (glimepiride) which antagonizes ABCC9 exacerbates HS-Aging pathology and abnormal behavior. 3. Test in the GRN-KO mouse model the hypothesis that nicorandil which opens the potassium channel (the opposite activity as sulfonylureas) reduces HS-Aging-related abnormal pathology and behavior. Since there are similar pathologies and genetic susceptibilities the therapeutic strategy may also be relevant to a separate lethal neurodegenerative disease frontotemporal lobar degeneration (FTLD).

project_terms:
ABCC9 gene;Address;Affect;Age;Aging;Agonist;Alzheimer's Disease;Amygdaloid structure;Animal Model;Antidiabetic Drugs;Apolipoprotein E;Astrocytosis;Attenuated;Autopsy;Behavior;Behavioral;Biochemical Markers;Biochemistry;Brain;Cells;Clinical;Clinical Data;Clinical Research;Clinical Trials;Controlled Study;Data;Diabetes Mellitus;Disease;Drug usage;Elderly;Exposure to;Frontotemporal Lobar Degenerations;Genetic Polymorphism;Genetic Predisposition to Disease;Genomics;Genotype;Glimepiride;Gliosis;Goals;Hippocampus (Brain);Human;Impaired cognition;Knockout Mice;Knowledge;Life;Link;Modeling;Morbidity - disease rate;Mus;Mutation;Neurodegenerative Disorders;Neurofibrillary Tangles;Nicorandil;Oral;Paper;Pathologic;Pathology;Patients;Persons;Pharmaceutical Preparations;Pharmacology;Potassium Channel;Pre-Clinical Model;Preclinical Testing;Proteins;Public Health;Publishing;Regulation;Research;Risk;Series;Sulfonylurea Compounds;Testing;Therapeutic;Transgenic Mice;Yin;age related;base;behavioral study;clinically relevant;genome wide association study;genome-wide;hippocampal sclerosis;mouse model;neurobehavioral;novel;novel therapeutics;pre-clinical;preclinical development;preclinical study;protein TDP-43;protein function;public health relevance;risk variant;volunteer

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Diseases that mimic Alzheimer's disease (AD) are understudied causes of cognitive impairment in the elderly. A common and high-morbidity "AD mimic" is HS-Aging and here we propose the first animal model of HS-Aging to test a novel therapeutic strategy. We will treat transgenic mice with a drug nicorandil as a preclinical "proo of concept" to reverse the HS-Aging related pathology and behavioral changes and which may also be relevant to a therapeutic approach for frontotemporal lobar degeneration (FTLD).


application_id: 9197893
project_number: 5R01DE017921-07
project_title: Role of JAKs in innate responses to P. gingivalis
administering_ic: NIDCR
award_notice_date: 2016-12-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DE
serial_number: 017921
program_official: CHANDER, PREETHI
project_start_date: 2010-06-23
project_end_date: 2019-12-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Inflammatory responses to pathogenic bacteria are essential for protection of the host and control of bacterial infection. However inflammatory responses that are sustained in duration and intensity can be damaging to susceptible tissues. To limit the ferocity of inflammation and curtail possible tissue damage a number of pathways exist that dampen the innate immune response. Our studies have focused on a tyrosine kinase of the Janus kinase (JAK) family JAK3. We have found that that challenge with the periodontal pathogen P. gingivalis increases both the activation state and the amount of JAK3 in human monocytes and murine bone marrow derived macrophages. Moreover JAK3 inhibition enhances the production of pro-inflammatory cytokines upon P. gingivalis stimulation and concurrently diminishes levels of the anti-inflammatory cytokine IL-10. Thus we have identified a novel role for JAK3 as a negative regulator of inflammation and propose that stimulation of this endogenous anti-inflammatory pathway in the host will help limit or prevent P. gingivalis- induced tissue destruction. The specific hypothesis to be tested in this application is that P. gingivalis-modified JAK3 activation in innate immune cells directs negative regulation of inflammation and ultimately controls alveolar bone loss through dedicated downstream signaling pathways. We will challenge this hypothesis with three specific Aims: 1) To characterize JAK3 signaling pathways that control anti-inflammatory responses induced by P. gingivalis; 2) To functionally dissect P. gingivalis modification of JAK3 expression and activationin innate immune cells; 3) To determine the effect of JAK3 inhibition in vivo on inflammatory responses and the disease process induced by P. gingivalis using a mouse chamber model and bone loss model. Successful completion of these studies will define for the first time the host anti-inflammatory responses to P. gingivalis that flow through JAK3. In addition this work will characterize an important but relatively understudied aspect of the overall host-P. gingivalis interaction and increase our understanding both of the role of JAK3 in innate immune cells and of anti-inflammatory mechanisms in general. This work could be translated into the identification of novel targets for therapeutic intervention designed to enhance anti-inflammatory signaling and prevent or limit tissue destruction. Such an approach has relevance both for periodontal disease and for chronic inflammatory conditions in general.

project_terms:
Adopted;Affect;Agonist;Alveolar Bone Loss;Anti-Inflammatory Agents;Anti-inflammatory;Autocrine Communication;Bacteria;Bacterial Infections;Bone Marrow;Cells;Chronic;Data;Disease;Equilibrium;Event;Family;Genetic Transcription;Gingiva;Goals;Health;Homeostasis;Human;Immune;Immune response;Impairment;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Interleukin-10;Interleukin-4;JAK3 gene;Janus kinase;Knock-in;Knockout Mice;Mass Spectrum Analysis;Mediating;Microbe;Modeling;Modification;Mus;Natural Immunity;Neutrophil Infiltration;Organism;Pathway interactions;Pattern;Periodontal Diseases;Periodontitis;Periodontium;Phosphorylation;Porphyromonas gingivalis;Process;Production;Protein Tyrosine Kinase;Proto-Oncogene Proteins c-akt;Regulation;Role;Signal Pathway;Signal Transduction;Signaling Protein;Site-Directed Mutagenesis;Testing;Time;Tissues;Translating;Work;bone loss;cytokine;design;immunoreaction;in vivo;knock-down;macrophage;member;microbial;microbial community;monocyte;new therapeutic target;novel;oral infection;pathogen;pathogenic bacteria;prevent;public health relevance;response;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: To protect against bacterial infection our bodies mount an inflammatory response; however this response must be regulated to prevent excessive inflammation and associated tissue damage. We have identified a host signaling protein called JAK3 that can dampen inflammatory responses to a gum disease causing organism. In this study we will characterize the role of JAK3 with the ultimate goal of designing means to stimulate this molecule and curtail inflammatory destruction in gum disease.


application_id: 9197283
project_number: 5R37DE011111-24
project_title: P.gingivalis interactions with gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2016-12-12
opportunity_number: PA-07-070
application_type: 5
activity_code: R37
ic: DE
serial_number: 011111
program_official: LUNSFORD, DWAYNE
project_start_date: 2014-01-01
project_end_date: 2018-12-31
study_section: NSS
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Periodontal diseases are one of the most common bacterial infections of humans and impose a significantburden on the health care system. One of the predominant pathogens in periodontal disease is P.gingivalis; however P. gingivalis can also inhabit the oral cavity in the absence of disease. The interactionbetween P. gingivalis and gingival epithelial cells makes a significant contribution to the degree ofequilibrium between host and microbe and to overall gingival health status. P. gingivalis can manipulateepithelial cell signal transduction pathways in order to direct entry into the host cell and to reprogram hostinnate immunity. One of the effector molecules of P. gingivalis is the HAD family serine phosphatase SerB.The goal of this proposal is define the outcomes of the interaction between P. gingivalis and gingivalepithelial cells as they relate colonization of the organism and the generation of immune dysbiosis. We shallalso continue our major focus on the role of the functionally versatile SerB invasin and modulin of P.gingivalis. Cofilin an actin depolymerizing protein is required for P. gingivalis invasion. We will examinethe ability of SerB to dephosphorylate and inactivate LIMK kinase which will lead to activation of cofilin. Wewill then investigate the impact of P. gingivalis on ROCK PAK1 and MK2 pathways that lead to activation of LIMK. These interactions will be observed within the cell by live cell imaging. P..gingivalis can suppressIL-8 production in part through regulation of actin dynamics. We shall study the cofilin dependent actinmediated suppression of IL-8 by P. gingivalis. The immune disruptive ability of P. gingivalis also extends toT-cell chemokines and the mechanism of suppression of IP-10 ITAC and Mig will be studied. We will alsobegin to assess biological relevance by examining T-cell migration in response to epithelial cells infectedwith P. gingivalis. These studies will provide a detailed molecular analysis of the targeting of host signaltransduction by P. gingivalis along with the role of a specific effector phosphatase. Ultimately the knowledge gained could be developed into strategies that could be utilized to intervene in the P.gingivalis-epithelial cell interaction to ensure that the outcome is non-harmful to the host.RELEVANCE (See instructions):P. gingivalis is a cause of periodontal diseases that afflict millions of Americans. In this study we willexamine the interactions between P. gingivalis and the human cells that are colonized by the organism. Theinformation to be gathered could be used to identify targets for novel therapeutic agents designed tointerfere with the colonization and survival strategies of P. gingivalis.

project_terms:
Actins;American;Bacterial Infections;Binding;Biological;Biological Assay;CXCL10 gene;Cell Communication;Cells;Complement;Data;Development;Disease;Elements;Ensure;Epithelial Cells;Equilibrium;Family;Generations;Gingiva;Goals;Health Status;Healthcare Systems;Human;I-kappa B Proteins;IL8 gene;IRF1 gene;Immune;Immunologic Surveillance;Infection;Interferons;Knowledge;LIM Domain Kinase 1;LIMK1 gene;Label;Lead;Location;Luciferases;MEK inhibition;Measurement;Measures;Mediating;Microbe;Molecular;Molecular Analysis;Natural Immunity;Nuclear Translocation;Oral cavity;Organism;Outcome;Pathway interactions;Periodontal Diseases;Phospho-Specific Antibodies;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Inhibition;Phosphotransferases;Plasmids;Porphyromonas gingivalis;Process;Production;Protein Dephosphorylation;Proteins;ROCK1 gene;Regulation;Reporter;Role;Serine;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;Small Interfering RNA;Structure;T-Lymphocyte;TNF gene;Testing;Therapeutic Agents;Transcriptional Regulation;Variant;actin depolymerizing proteins;cell motility;chemokine;cofilin;design;in vivo;live cell imaging;mutant;new therapeutic target;novel therapeutics;overexpression;p65;pathogen;prevent;promoter;response;transcription factor

public_health_relevance:
RELEVANCE (See instructions):P. gingivalis is a cause of periodontal diseases that afflict millions of Americans. In this study we willexamine the interactions between P. gingivalis and the human cells that are colonized by the organism. Theinformation to be gathered could be used to identify targets for novel therapeutic agents designed tointerfere with the colonization and survival strategies of P. gingivalis.


application_id: 9197262
project_number: 5R21AI122078-02
project_title: Blocking RNA virus replication through the antiviral functions of cellular helicases
administering_ic: NIAID
award_notice_date: 2016-11-23
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 122078
program_official: PARK, EUN-CHUNG
project_start_date: 2015-12-17
project_end_date: 2018-11-30
study_section: Virology - A Study Section[VIRA]
contact_pi_person_id: 7353039
contact_pi: NAGY, PETER
other_pis: Not Applicable
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Blocking RNA virus replication through the antiviral functions of cellular helicases. A recently emerging concept in innate immunity is the significant roles of cell-intrinsic restriction factors (CIRFs) against several viruses which are expressed bythe host cells. CIRFs greatly reduce virus replication and facilitate combating viruses and making the induced and passive innate immune responses more potent. The PI has identified cellular DEAD-box helicases as strong CIRFs against an RNA virus. RNA helicases are involved in all aspects of cellular metabolism and perform RNA duplex unwinding and remodeling of RNA-protein complexes in cells. Dissecting the mechanism of antiviral function of cellular helicases promises a new avenue to develop effective antiviral strategies against plant and possibly animal viruses Progress in our understanding of the mechanisms of host factors is greatly accelerated by the use of easily tractable virus - host systems such as Tomato bushy stunt virus (TBSV) and yeast model. The PI will identify and characterize the most potent cellular helicases to block plant and insect virus replication. The proposal will focus on two cellular helicases that showed the most potent antiviral effect thus justifying the potential of tis novel approach. The following are the major strengths of the proposal: (i) Viral RNA replication is clearly of immense importance for viruses to infect living organisms. (ii) The combination of yeast and authentic cell-free assay developed by the PI is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication and viral pathogenesis. (iii) Cellular helicases are emerging as major cell-intrinsic restriction factors against several viruses (iv) This work has the potential to obtain a novel effective antiviral approach that has several advantages over traditional viral targets. The advantages include broader antiviral effects against many related and possibly even unrelated viruses and more durable antiviral effects. Developing an efficient antiviral strategy based on blocking viral replication via cellular helicass could rapidly be done in this elegant tombusvirus-yeast system. Based on the possible broad antiviral effect of these cellular helicases which are highly conserved from plants to animals research can then adapt the gained knowledge and methods for other animal human and plant viruses. The research holds promise of benefiting society by leading to groundbreaking results in the area of virus replication host-virus interactions and the adaptation of viruses to their hosts.

project_terms:
Animal Experimentation;Animals;Antiviral Agents;Area;Biological Assay;Cell physiology;Cells;Complex;Human;Infection;Innate Immune Response;Insect Viruses;Integration Host Factors;Knowledge;Metabolism;Methods;Modeling;Natural Immunity;Organism;Plant Viruses;Plants;Protein Family;RNA;RNA Helicase;RNA Viruses;RNA replication;Research;Role;Societies;System;Tombusviridae;Tombusvirus;Viral;Viral Pathogenesis;Virus;Virus Replication;Work;Yeast Model System;Yeasts;base;combat;fighting;frontier;genome-wide analysis;helicase;novel;novel strategies;pathogen;protein complex;public health relevance;replicase;tomato bushy stunt virus;tool;viral RNA;virology;virus host interaction

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A recently emerging concept in innate immunity is the significant roles of cell-intrinsic restriction factors against several viruses which are expresse by host cells. The PI has identified cellular DEAD-box helicases as antiviral factors against an RNA virus. The proposed work will unravel the antiviral functions of two cellular helicases.


application_id: 9196769
project_number: 1R21AI126883-01
project_title: Borrelia miyamotoi: mechanisms of tick colonization and transmission
administering_ic: NIAID
award_notice_date: 2016-06-15
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 126883
program_official: ILIAS, MALIHA R
project_start_date: 2016-07-01
project_end_date: 2018-06-30
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTHuman infection by the spirochete Borrelia miyamotoi is a newly-recognized public health threat in the US andother parts of the world. Borrelia miyamotoi infection may require hospitalization with symptoms that includehigh fever joint and muscle pain and meningoencephalitis. B. miyamotoi is spread by the bites of infectedIxodes spp. ticks but almost nothing is known about how or where the bacterium colonizes its vector or thedynamics of transmission. This proposal brings together an expert team of Borrelia and tick researchers whowill conduct a series of synergistic studies that will greatly expand understanding of B. miyamotoi transmissionand infection mechanisms.

project_terms:
Acute;Address;Adult;Anaplasma phagocytophilum;Area;Argasidae;Arthralgia;Babesia;Bacteria;Biology;Bite;Black-legged Tick;Borrelia;Borrelia burgdorferi;Borrelia miyamotoi;Climate;Diagnosis;Ehrlichia;Emerging Communicable Diseases;Exhibits;Exposure to;Fever;Geographic Locations;Health;Horizontal Disease Transmission;Hospitalization;Hour;Human;Immunocompromised Host;Incidence;Infection;Institute of Medicine (U.S.);Invaded;Ixodes;Ixodidae;Laboratories;Larva;Location;Lyme Disease;Maintenance;Meningoencephalitis;Midwestern United States;Myalgia;New England;Nymph;Ohio;Order Spirochaetales;Ornithodoros;Population;Prevalence;Proteins;Public Health;Publishing;Relapsing Fever;Reporting;Research Personnel;Risk;Rivers;Sampling;Seminal;Series;Seroprevalences;Site;Spirochaetales Infections;Staging;Symptoms;Tick-Borne Diseases;Tick-Borne Encephalitis Virus;Tick-Borne Encephalitis Viruses;Tick-Borne Infections;Ticks;Time;Vertical Disease Transmission;Widespread Disease;differential expression;disorder prevention;exposed human population;feeding;field study;laboratory experiment;land use;pathogen;relapsing fever borrelia;transmission process;vector

public_health_relevance:
PROJECT NARRATIVEHuman infection by the tick-borne bacterium Borrelia miyamotoi has recently been recognized as a threat tohuman health. Currently very little is currently known about how B. miyamotoi is transmitted by its tick vector.This proposal brings together three experts in tick and Borrelia biology who will conduct a series of studiesthat will reveal mechanisms by which B. miyamotoi colonizes its tick vector and is transmitted to mammalianhosts.


application_id: 9196481
project_number: 1R01EY026158-01A1
project_title: Cone Rescue in Retinitis Pigmentosa
administering_ic: NEI
award_notice_date: 2016-08-24
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: EY
serial_number: 026158
suffix: A1
program_official: NEUHOLD, LISA
project_start_date: 2016-09-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1 BDCN-W (04)]
contact_pi_person_id: 1898524
contact_pi: KAPLAN, HENRY JERROLD
other_pis: DEAN, DOUGLAS CHASE;MCCALL, MAUREEN A
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
ARHGEF5 gene;Adult;Animal Model;Area;Binding;Birth;Blindness;Cell Transplants;Cells;Color Visions;Cone;Disabled Persons;Disease;Endoplasmic Reticulum;Evaluation;Face;Family member;Family suidae;Gene Transfer;Genes;Glucose;Inherited;Label;Leber's amaurosis;Light;Mitochondria;Modeling;Mus;Mutation;Neuroprotective Agents;Night Blindness;North America;Opsin;Patients;Peripheral;Pharmacotherapy;Population;Prevention;Process;Reading;Resolution;Retina;Retinal Cone;Retinal Degeneration;Retinal Diseases;Retinal Pigments;Retinitis Pigmentosa;Rhodopsin;Rod Outer Segments;Series;Source;Staging;Starvation;Symptoms;TXN gene;Therapeutic;Time;Transplantation;Vertebrate Photoreceptors;Vision;Visual;Visual Fields;abstracting;base;cone-rod degeneration;fetal;gene therapy;glucose transport;glucose uptake;handicapping condition;hereditary blindness;in vivo;induced pluripotent stem cell;macula;man;mutant;neuroprotection;overexpression;prevent;restoration;retinal rods;sensor


application_id: 9195808
project_number: 2R01DC007176-12
project_title: Neurotrophin receptor regulation of adult taste bud innervation and function
administering_ic: NIDCD
award_notice_date: 2016-07-08
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZRG1 IFCN-B (03)]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adult;Agonist;Basic Science;Brain;Brain-Derived Neurotrophic Factor;Cells;Chemicals;Citric Acid;Clinical;Defect;Development;Disease;Electrophysiology (science);Excision;Eye;Fiber;Food;Ganglia;Genetic;Goals;Health;Ion Channel;Knock-out;Label;Location;Mus;Nerve;Nerve Fibers;Nerve Growth Factor Receptors;Nerve Regeneration;Neuromodulator;Neurons;Neurotransmitter Receptor;Neurotrophic Tyrosine Kinase Receptor Type 2;Pathway interactions;Pattern;Peripheral;Persons;Process;Quality of life;Receptor Cell;Regulation;Resolution;Role;Sensory;Signal Transduction;Sodium Chloride;Specificity;Stimulus;Structure of geniculate ganglion;Taste Bud Cell;Taste Buds;Taste Disorders;Taste Perception;Techniques;Testing;Therapeutic;Three-Dimensional Imaging;Three-dimensional analysis;Time;Transgenic Mice;Tyrosine Kinase Inhibitor;abstracting;base;cell type;chemical genetics;epithelial Na+ channel;ganglion cell;genetic approach;nerve supply;neurotrophic factor;receptor;relating to nervous system;research study;response;sensory system;small molecule;taste system


application_id: 9195802
project_number: 1R01AG054130-01
administering_ic: NIA
award_notice_date: 2016-07-07
opportunity_number: PAR-16-365
application_type: 1
activity_code: R01
ic: AG
serial_number: 054130
program_official: MCLINDEN, KRISTINA
project_start_date: 2016-07-15
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1 BBBP-V (55)]
contact_pi_person_id: 10700978
contact_pi: MOGA, DANIELA CLAUDIA
other_pis: JICHA, GREGORY A
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-15
project_terms:
AD pathology;Address;Adverse drug effect;Aerobic Exercise;Affect;Age;Alzheimer's Disease;Alzheimer's disease risk;American;Amyloid;Anti-Cholinergics;Beer;Biological;Brain;Clinical;Cognitive;Communities;Complex;Data;Dementia;Diet;Disease;Disease Progression;Drug usage;Elderly;Enrollment;Expenditure;Health;Health Care Costs;Health Expenditures;Healthcare;Impaired cognition;Intervention;Intervention Trial;Life;Measures;Medical;Medication Management;Neurocognitive;Neurofibrillary Tangles;Onset of illness;Outcome Measure;Pathologic;Pathology;Patients;Pharmaceutical Preparations;Pharmacists;Pharmacy facility;Phase;Physicians;Placebos;Population;Positron-Emission Tomography;Prevalence;Prevention strategy;Public Health;Reporting;Research;Scopolamine;Senile Plaques;Societies;Symptoms;Testing;Time;United States;aging population;base;clinical practice;cognitive reserve;disability;exhaust;functional decline;human old age (65+);indexing;insight;non-demented;older patient;patient oriented;post intervention;pre-clinical;primary outcome;psychosocial;public health relevance;randomized placebo controlled trial;randomized trial;reduce symptoms;stressor;therapy design;uptake


application_id: 9194759
project_number: 1R13ES027338-01
project_title: 2016 Princess Chulabhorn International Science Congress
administering_ic: NIEHS
award_notice_date: 2016-06-22
opportunity_number: PA-13-347
application_type: 1
activity_code: R13
ic: ES
serial_number: 027338
program_official: HEACOCK, MICHELLE
project_start_date: 2016-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZES1 JAB-D (S3)]
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe Princess Chulabhorn International Science Congress conference series is an important platform forcontinuing the coordination of US and Southeast Asian stakeholder expertise directed at multiple facets ofenvironmental health. The University of Kentucky Superfund Research Center (UK-SRC) led by Dr. BernhardHennig proposes to partner with other Superfund Research Centers to develop and implement a special focusnutrition symposium within this conference program. Conference dates are November 13-17 2016 at theShangri-La Hotel in Bangkok Thailand. The overarching objective of the proposed special focus nutritionsymposium is to facilitate scientific exchange within an emerging prevention paradigm better define thecomplex but common links between health and environment particularly within Southeast Asian countries andenable use of shared understandings of current research. To help accomplish the goals of the nutritionsymposium of tackling environmental pollution and associated disease risks in Southeast Asia throughnutritional interventions we propose the following four specific aims: (1) to compare and assess populationhealth impacts associated with infectious agents to advance the field of exposure science and to preventenvironmental disease through multi-level interventions and new risk-assessment paradigms that includenutrition or healthful diets; (2) to examine multiple environmental stressors and health status as a variant ofdisease by studying persistent organic pollutants metals mixtures and new and emerging pollutants that existin Southeast Asia; (3) to facilitate intellectual exchange among scientists and trainees in the health andenvironmental science fields by identifying innovative sustainable strategies for using nutrition to modulateenvironmental stressors; and (4) to provide a platform for strengthening collaborations between US andSoutheast Asian trainees and early-career environmental scientists who tackle 21st century environmentalchallenges. The conference objectives of this special nutrition symposium will be accomplished by inviting fivesession speakers from the US and/or Southeast Asian nations to participate. In addition to the oralpresentations a poster session with a similar nutrition focus will maximize the interactions students andtrainees have with more established scientists and stakeholders. The outcomes from the special nutritionsymposium include defining the current state of the field of health and the environment identifying knowledgegaps promoting collaborative research and publishing the outcomes that result from the symposium.

project_terms:
Adopted;Agriculture;Air Pollution;Asians;Award;Biological;Brunei;Burn injury;Chemical Exposure;Chemicals;Collaborations;Complex;Congresses;Congresses and Conferences;Country;Coupled;Developing Countries;Diet;Dietary Intervention;Disease;Education;Environment;Environmental Health;Environmental Pollutants;Environmental Pollution;Exposure to;Fire - disasters;Goals;Health;Health Status;Human;Incidence;Individual;Indonesia;Infectious Agent;Institution;International;Intervention;Kentucky;Knowledge;Link;Longevity;Malnutrition;Metals;Minority;National Institute of Environmental Health Sciences;Oral;Outcome;Pathogenesis;Pathway interactions;Philippines;Pollution;Poverty;Predisposition;Prevention;Publishing;Recording of previous events;Research;Research Personnel;Risk;Risk Assessment;Role;Science;Scientist;Series;Smoke;Southeastern Asia;Students;Superfund;Techniques;Thailand;Therapeutic Intervention;Travel;Universities;Variant;Vietnam;Virus Diseases;Woman;career;cost;disorder risk;environmental chemical exposure;environmental stressor;exposed human population;farmer;forest;innovation;interest;neglect;nutrition;persistent organic pollutants;pollutant;population health;posters;prevent;programs;remediation;southeast Asian;symposium

public_health_relevance:
PROJECT NARRATIVEThe 2016 Princess Chulabhorn International Science Congress to be held November 13-17 2016 inBangkok Thailand will provide an ideal setting to discuss and tackle challenges of reducing/preventing healthrisks associated with exposure to diverse environmental contaminants in Southeast Asia. The special nutritionsymposium theme that we are proposing will focus on prevention paradigms that utilize nutrition to reduce andmodulate environmental insults.


application_id: 9194491
project_number: 1R13NS098720-01
project_title: National Neurotrama Symposium 2016
administering_ic: NINDS
award_notice_date: 2016-06-06
opportunity_number: PA-13-347
application_type: 1
activity_code: R13
ic: NS
serial_number: 098720
program_official: LAVAUTE, TIMOTHY M
project_start_date: 2016-06-15
project_end_date: 2016-08-21
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
contact_pi_person_id: 7875161
contact_pi: SNOW, DIANE M
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Neurotrauma is the largest cause of death and disability for persons under the age of 45 in theworld and the societal cost of the resulting disability exceeds $60 billion per year in the United Statesalone. The National Neurotrauma Society (NNS) annual symposium now in its 34th year is theprimary forum for the exchange of information in the fields of traumatic brain injury (TBI) and spinalcord injury (SCI) and a means of integrating new information regarding the pathophysiology andtreatment of TBI and SCI. This application seeks funding to support 20 pre- and postdoctoraltrainees to attend the Symposium as well as partial support for travel of 102 invited speakers (whichwill be distributed equitably by consensus of the Program Planning Committee.) The meeting will beheld in Lexington KY at the downtown Lexington Convention Center and Hyatt. The 4-day meetingwill focus on important and timely topics in the field of neurotrauma including basic translationaland clinical investigations. Given that Lexington KY is the horse capital of the world and given thefocus of the meeting the conference is entitled: The Triple Crown: Advances in Basic SciencesPre-clinical Modeling and Clinical Approaches. For the 6th year in a row the 2016 meeting will be co-hosted by the NNS and the AANS/CNS JointSection on Neurotrauma and Critical Care (AANAS/CNS JSNCC). Members from both societies areincluded on the Program Planning Committee to ensure a sufficient mix of topics targeting both TBIand SCI and both basic science and clinical research. This arrangement successfully closes thegap by bringing together clinicians and basic scientists to network share concerns and createsolutions. An exciting collection of state-of-the-art sessions on the consequences of damage to the nervoussystem and treatment strategies for protection and repair are planned  some that get attentionannually and others that are novel and innovative. Plenary session topics include: discussions byworld experts on concussion and on clinical trial design the acute cellular pathophysiology ofneurotrauma engineering approaches for functional restoration after SCI advances challenges andopportunities in CNS regeneration a primer on imaging from animals to humans big dataapproaches to neurotrauma and emerging therapeutics for neurotrauma. Symposia or break-outsessions will cover a wide variety of other important topics that will be of great interest to scientistsand clinicians. Further specialty events include: a trainee Data Blitz a discussion on careers inscience a Patient's Perspective segment networking and team-building exercises for trainees andan interactive project on the lifecycle of the society to promote attendee interaction and involvement.

project_terms:
Accident and Emergency department;Acute;Age;Age-Years;American;Animal Model;Arts;Attention;Autonomic Dysfunction;Awareness;Basic Science;Battered Women;Big Data;Biological Markers;Blast Cell;Brain;Brain Concussion;Capital;Career Choice;Caring;Cause of Death;Chronic;Clinical;Clinical Medicine;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Communication;Congresses;Consensus;Critical Care;Data;Dental crowns;Diagnosis;Educational workshop;Engineering;Ensure;Equus caballus;Event;Exercise;Fathers;Fostering;Functional disorder;Funding;Goals;Grant;Housing;Human;Image;Individual;Injury;Intervention;Joints;Knowledge;Laboratories;Life;Medical;Medical Students;Mentors;Mentorship;Minority;Mothers;Names;Natural regeneration;Nervous System Trauma;Nervous system structure;Neurologic;Nurses;Pathogenesis;Pathologic Processes;Patients;Persons;Plant Roots;Population Heterogeneity;Pre-Clinical Model;Recovery;Research;Research Methodology;Research Personnel;Respiratory physiology;Rewards;Science;Scientist;Sex Characteristics;Societies;Spinal Cord;Spinal cord injury;Standardization;Students;Surgeon;Surveys;Techniques;Therapeutic;Thinking;Translating;Traumatic Brain Injury;Travel;United States;Woman;Work;abstracting;animal imaging;career;central nervous system injury;clinical investigation;cost;disability;functional restoration;graduate student;human subject;innovation;insight;interest;learning network;medical specialties;meetings;member;mild traumatic brain injury;neuropathology;neurosurgery;novel;physical abuse;pre-doctoral;profession allied to medicine;programs;repaired;research to practice;restoration;symposium;treatment strategy;undergraduate student

public_health_relevance:
Project Narrative Over 1.8 million new cases of traumatic brain injury present to emergency rooms in the UnitedStates and over 50000 die each year and 12000 new cases of spinal cord injury occur in theUnited States with many of these individuals living with chronic disabilities. Neurotrauma is thelargest cause of death and disability for persons under 45 years of age in the world and thesocietal costs of these neurotrauma disabilities exceed $60 billion per year. Currently there arelimited treatments that can protect against the devastating consequences of TBI or interventionsto promote recovery after injury.


application_id: 9194461
project_number: 1R13ES027336-01
project_title: The 9th Conference on Metal Toxicity and Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2016-07-07
opportunity_number: PA-13-347
application_type: 1
activity_code: R13
ic: ES
serial_number: 027336
program_official: REINLIB, LESLIE J
project_start_date: 2016-08-01
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZES1 JAB-D (C3)]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: LIU, KE JIAN
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe 9th Conference on Metal Toxicity and Carcinogenesis will be held at Hilton Lexington DowntownLexington Kentucky October 23-26 2016. We propose to continue this biennial conference series whichsince its inception 16 years ago has become the premier international conference in the field of metal toxicityand carcinogenesis. This meeting will be sponsored by the University of Kentucky the UK College of Medicineand the UK Markey Cancer Center. This interdisciplinary scientific conference is a workshop that bringstogether a community of scientists from across the United States and overseas that focuses its research onmetal toxicity and carcinogenicity. The objectives of the meeting are 1) to coordinate exchange anddisseminate information and 2) to explore metal-induced toxicity and carcinogenicity. The focuses will bemechanisms of metal-induced toxicity strategies for intervention and prevention and possible translation frombasic studies into clinical or public policy. The conference content will challenge and seek to shift currentresearch paradigms or employ novel approaches or methods to fulfill its purpose. To achieve these goals theconference will cover concepts approaches or methodologies instrumentation or interventions novel to thefield of metal toxicity and carcinogenicity as well as in a broad sense. The conference will also address arefinement improvement or new application of theoretical concepts approaches or methodologiesinstrumentation or interventions. The Conference will stimulate interactions of scientists and collaboration andhelp move the field forward.

project_terms:
Address;Area;Cancer Center;Clinical;Collaborations;Communities;Educational workshop;Fees;Funding;Goals;International;Intervention;Kentucky;Medicine;Metal Carcinogenesis;Metals;Methodology;Methods;Minority Graduate Student;Preventive Intervention;Public Policy;Research;Scientist;Series;Toxic effect;Translations;Underrepresented Groups;United States;Universities;carcinogenesis;carcinogenicity;college;instrumentation;meetings;metal poisoning;minority undergraduate;novel;novel strategies;symposium;waiver

public_health_relevance:
NARRATIVEThe 9th Conference on Metal Toxicity and Carcinogenesis will be held at HiltonLexington Downtown Lexington Kentucky October 23-26 2016. The Conference is aworkshop that brings together a community of scientists in the area of metal toxicity andcarcinogenicity from around the U.S. and some from overseas. The goals of themeeting are to coordinate exchanges and disseminate information and to exploremechanisms of metal-induced toxicity and carcinogenicity.


application_id: 9194017
project_number: 1R01AG053999-01
project_title: Role of Systemic Amylin Dyshomeostasis in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2016-09-05
opportunity_number: PAR-15-358
application_type: 1
activity_code: R01
ic: AG
serial_number: 053999
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2016-09-15
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1 MDCN-C (56)]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
4 hydroxynonenal;Abeta clearance;Aging;Alleles;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Animal Model;Apolipoprotein E;Binding;Biological Markers;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Injuries;CREB1 gene;Carnosine;Cell Culture Techniques;Cell model;Cerebrospinal Fluid;Cerebrovascular Circulation;Clinical Data;Data;Dementia;Deposition;Diagnosis;Disease Progression;Early Onset Familial Alzheimer's Disease;Eicosanoids;Etiology;Figs - dietary;Genotype;Goals;Hormones;Human;Hypertrophy;Impaired cognition;Inflammatory;Injection of therapeutic agent;Injury;Interleukin-1 beta;Intervention;Kentucky;Knock-out;Knowledge;Late Onset Alzheimer Disease;Lead;Link;Lipid Peroxidation;London;Low-Density Lipoproteins;Malondialdehyde;Measures;Mediating;Medical Research;Membrane;Metabolic;Metabolic Diseases;Modeling;Neurologic Deficit;Non-Insulin-Dependent Diabetes Mellitus;Pancreas;Pancreatic Hormones;Pathology;Pathway interactions;Patients;Peptides;Pharmacologic Substance;Physiological;Plasma;Prevention strategy;Property;Protein Isoforms;Rattus;Research Project Grants;Rest;Risk Factors;Role;Signal Transduction;Smooth Muscle Myocytes;Specimen;Testing;Therapeutic;Toxic effect;Transgenic Animals;Universities;Vascular Diseases;Work;abstracting;apolipoprotein E-4;brain tissue;cerebrovascular;clinically relevant;college;cytotoxicity;diabetic;diabetic rat;human data;human disease;human tissue;inhibitor/antagonist;insight;islet amyloid polypeptide;lipid peroxidation inhibitor;mutation carrier;nervous system disorder;neuroinflammation;neurotoxicity;neurovascular unit;novel;presenilin-1;prevent;repository;research study;therapeutic target


application_id: 9193873
project_number: 4R00EY024336-03
project_title: Non-canonical NLRP3 Inflammasome Activation in Geographic Atrophy
administering_ic: NEI
award_notice_date: 2015-12-25
opportunity_number: PA-11-197
application_type: 4
activity_code: R00
ic: EY
serial_number: 024336
program_official: MCKIE, GEORGE ANN
project_start_date: 2016-01-01
project_end_date: 2016-06-30
study_section: NSS
contact_pi_person_id: 11044965
contact_pi: KERUR, NAGARAJ
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This K99/R00 grant will facilitate the applicant's (Dr. Nagaraj Kerur) long-term goal to develop as an independent investigator in vision research. Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) characterized by central loss of vision due to retinal pigmented epithelium (RPE) degeneration. Currently there is no therapy available for GA because of its unclear etiology. We recently discovered that DICER1 deficit causes a pathologic accumulation of Alu RNA transcripts in the RPE of human GA eyes and that the accumulated Alu RNAs activate the NLRP3 inflammasome which in turn leads to IL- 18/MyD88-dependent RPE cell death (Kaneko et al. Nature 2011; Tarallo et al. Cell 2012). In exciting new preliminary studies we have discovered that Alu RNA-induced NLRP3 inflammasome activation occurs in a non-canonical fashion- a newly described pathway in which caspase 4 (aka caspase 11 in mouse) is required for the NLRP3 inflammasome activation (in contrast the canonical inflammasome activation is independent of caspase 4). The central goal of the proposed research is to define role of caspase 4-mediated non-canonical NLRP3 inflammasome activation in the context of GA and to identify critical signaling pathways regulating caspase 4 activation via the following aims: (1) Define the signaling pathways that regulate caspase 4 (aka caspase 11 in mouse) activation by Alu RNA; (2) Elucidate the mechanisms of caspase 4 (aka caspase 11 in mouse) activation of the NLRP3 inflammasome; and (3) Measure the activation of these non-canonical inflammasome signaling pathways in human GA. These studies will illuminate the molecular foundation of GA unravel novel regulatory checkpoints of NLRP3 inflammasome activation and provide a strong molecular foundation for exploiting new therapeutic targets in AMD. During the mentored phase (K99) the applicant will carry out the proposed studies under direct supervision of the mentor Dr. Jayakrishna Ambati at the University of Kentucky. In addition an advisory committee consisting of co-mentor Dr. Katherine Fitzgerald and the faculty members at the Department of Ophthalmology and Visual Sciences will monitor the applicant's research progress and offer assistance in advancing the applicant's transition towards independent investigator. The Ambati Group at the University of Kentucky as well as the Fitzgerald Laboratory at the University of Massachusetts Medical School both offer scientifically enriching environments and resources necessary for the advancement of the applicant's scientific career. The major focus of K99 phase will include: (1) mentored research to define molecular insights into the caspase 4 activation mechanism and to optimize experimental conditions for studies to be carried out in the R00 phase; and (2) training activities consisting of formal course work seminars workshops on grant writing and acquisition of other skill-sets required for successfully developing and leading an independent research program. During the R00 phase the focus will be on: (1) deciphering the mechanisms by which caspase 4 regulates NLRP3 inflammasome activation; and (2) quantifying the activation of non-canonical inflammasome signaling pathways in human GA eyes. Overall this proposal will not only unravel the novel molecular mechanisms of RPE degeneration in GA but will also equip the applicant with suitable skills to transition int an independent career in vision research.

project_terms:
Advisory Committees;Age related macular degeneration;Atrophic;Blindness;CASP1 gene;Caspase;Cell Culture Techniques;Cell Death;Cells;Cellular biology;Cessation of life;DICER1 gene;Dependency;Development;Disease;Educational workshop;Environment;Etiology;Eye;Faculty;Foundations;Goals;Grant;Health;Human;IL18 gene;Immune;Interferons;Interleukin-1;Interleukin-18;Investigation;Kentucky;Laboratories;Massachusetts;Measures;Mediating;Mentors;Modeling;Molecular;Monitor;Mus;Nature;Ophthalmology;Pathogenesis;Pathologic;Pathway interactions;Phase;Pilot Projects;Play;Proteomics;RNA;Regulation;Regulatory Pathway;Research;Research Personnel;Resources;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Structure of retinal pigment epithelium;Supervision;Therapeutic;Tissue Model;Training Activity;Transcript;Universities;Vision research;Work;Writing;age related;career;cytokine;geographic atrophy;human tissue;insight;macula;medical schools;member;mouse model;new therapeutic target;novel;programs;skills;vision science

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Recently we have discovered that the over-activation of the NLRP3 inflammasome pathway plays an essential role in the development of geographic atrophy (GA) an untreatable cause of blindness. However the mechanisms that govern inflammasome activation in GA are poorly understood. Our proposed research will help gain a deeper understanding of these inflammasome-regulatory pathways to identify novel critical molecules that can be targeted for treating GA and other inflammasomopathies.


