# projects

application_id: 9108234
project_number: 5R01AA020265-05
project_title: Role of Siah1 in ethanol-induced apoptosis and teratogenesis
administering_ic: NIAAA
award_notice_date: 2016-06-15
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AA
serial_number: 020265
program_official: HERELD, DALE
project_start_date: 2012-07-05
project_end_date: 2019-06-30
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
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): Prenatal ethanol exposure is the leading known cause of mental retardation. Growing evidence suggests that excessive cell death is a major component of the pathogenesis of ethanol-induced birth defects. However there is a fundamental gap in understanding how ethanol leads to apoptotic cell death in embryos. Continued existence of this gap represents an important problem because until it is filled understanding of ethanol- induced apoptosis that leads to teratogenesis will remain largely incomprehensible. Our long-term goal is directed toward the development of effective strategies against ethanol's teratogenesis; strategies based on prevention of ethanol-induced apoptosis through targeting specific proteins involved in apoptosis. The overall objective of this particular proposal is to establish Siah1 a member of the seven in absentia homology family as a feasible target for the prevention of ethanol-induced apoptosis and teratogenesis. The central hypothesis to be tested is that Siah1 mediates ethanol-induced apoptosis in neural crest cells (NCCs) by activating the p53 pathway and that the inhibition of Siah1-mediated apoptosis can prevent ethanol-induced teratogenesis. Our hypothesis has been formulated on the basis of strong preliminary data produced in our laboratory. To test our hypothesis the following specific aims will be addressed: Aim1: To characterize the role of Siah1 in ethanol-induced apoptosis in NCCs. We will determine the effects of ethanol on Siah1 mRNA and protein expression and investigate the potential of ethanol to promote Siah1 nuclear translocation and induce apoptosis. Aim2: To test the hypothesis that Siah1 mediates ethanol-induced apoptosis in NCCs by activating the p53 pathway. This will be accomplished by determining the role of Siah1 in ethanol-induced activation of p53 signaling pathway and in the induction of p53 downstream proapoptotic proteins and apoptosis. Aim3: To define the role of the inhibition of Siah1 function in conferring protection against ethanol-induced teratogenesis. This will be accomplished by using whole embryo culture Siah1 knockout mice and an oral intake FASD model. We will determine whether knocking down Siah1 diminishes ethanol-induced malformations in cultured mouse embryos and whether Siah1 deficiency in Siah1-/- mouse embryos can confer in vivo protection against ethanol-induced teratogenesis. The proposed work is innovative because it focuses on a novel approach targeting specific proteins directly involved in the apoptotic pathway to preventing ethanol-induced apoptosis and teratogenesis. The theoretical concept described in the application is also highly innovative because this is the first study attempting to prevent ethanol-induced apoptosis and teratogenesis specifically through the newly recognized actions of Siah1 in apoptosis. The results from this study will be significant because the insights gained by the accomplishment of these aims will help in elucidating the role of Siah1 in mediating ethanol- induced teratogenesis. They are also expected to yield strategies for the prevention of ethanol's teratogenesis and to fundamentally advance the field of FASD research.

project_terms:
Acetylation;Address;Alcohol consumption;Alcohols;Antioxidants;Apoptosis;Apoptotic;Brain;Brain region;Cell Cycle Arrest;Cell Death;Cell Line;Cell physiology;Cells;Cessation of life;Congenital Abnormality;Data;Development;Disease model;EP300 gene;Embryo;Ethanol;Family;Fetal Alcohol Exposure;Fetal Alcohol Spectrum Disorder;Goals;Human;Intake;Knockout Mice;Knowledge;Laboratories;Life;MAPK8 gene;Mediating;Mental Retardation;Mission;Molecular;Molecular Target;Mus;Neural Crest Cell;Neurons;Nuclear Translocation;Oral;Pathogenesis;Pathway interactions;Phosphorylation;Population;Prevention;Prevention strategy;Preventive Intervention;Proteins;Public Health;Research;Role;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;Staging;TP53 gene;Tertiary Protein Structure;Testing;Therapeutic;Therapeutic Intervention;Third Pregnancy Trimester;Work;alcohol effect;alcohol exposure;base;effective intervention;embryo culture;fetal;in vivo;innovation;insight;knock-down;mRNA Expression;malformation;member;non-genetic;novel strategies;novel therapeutics;p53 Signaling Pathway;prevent;protein expression

public_health_relevance:
The proposed research is relevant to public health because the insights gained by the accomplishments of the proposed studies will help in elucidating the mechanisms underlying ethanol-induced cell death and validating possible molecular targets for the development of novel therapeutics for the prevention of human Fetal Alcohol Spectrum Disorders (FASD). Thus the proposed research is relevant to the NIAAA's mission that pertains to using knowledge gained in uncovering target sites for alcohol's action on the embryonic and fetal stages of life to begin developing potential therapeutic or preventative interventions.


application_id: 9107488
project_number: 5R21HD079747-02
project_title: A Brain-Machine Interface to Facilitate Motor Recovery from Incomplete SCI
administering_ic: NICHD
award_notice_date: 2016-07-12
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: HD
serial_number: 079747
program_official: MARDEN, SUSAN F
project_start_date: 2015-07-08
project_end_date: 2018-12-31
study_section: Motor Function, Speech and Rehabilitation Study Section[MFSR]
contact_pi_person_id: 9484873
contact_pi: SUNDERAM, SRIDHAR
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Recent research suggests that neuroplasticity plays a crucial role in functional recovery after neurological injury. Sensory input in the form of sustaind peripheral nerve stimulation (PNS) can up-modulate neuroplastic change and thereby accelerate recovery of motor function. Furthermore our preliminary data demonstrate that motor function can be substantially enhanced when PNS is delivered prior to motor training. During PNS subjects remain awake but not actively engaged in any task. The objective of this project is to test whether PNS in subjects with incomplete spinal cord injury can accelerate recovery of motor function when PNS is delivered in closed-loop: i.e. only in response to subject's volition. This brief PNS delivery will be triggered by a brain-machine interface (BMI) that detects intent-to-move from suppression of the electroencephalogram (EEG) sensorimotor ("mu") rhythm which can occur with actual or imagined movement effort. Evidence of a beneficial effect from synchronizing PNS with intent-to-move could help optimize timing- dependent neuroplasticity which is critical for motor learning. This proposal has the following specific aims: 1. Develop a BMI for accurately detecting intent-to-move with minimal latency from continuous EEG measurements and briefly triggering closed-loop PNS in response to intent-to-move; and 2. Test the hypothesis that closed-loop PNS can promote motor neuroplasticity better than open-loop (pre-programmed) PNS or sham PNS as reflected by progressive increase in motor-evoked potential amplitude and motor performance. No study to date has investigated closed-loop PNS in individuals with neurological injuries. Refinement of PNS techniques and protocols that incorporate BMIs will contribute enormously to science and clinical care and therefore have high translational potential for neurorehabilitation.

project_terms:
Acute;Area;Body part;Brain;Corticospinal Tracts;Data;Detection;Development;Discriminant Analysis;Electric Stimulation;Electroencephalogram;Evaluation;Exercise;FPS-FES Oncogene;Fiber;Force of Gravity;Goals;Hand;Health;Imagery;Individual;Learning;Long-Term Potentiation;Measurement;Measures;Monitor;Motor;Motor Cortex;Motor Evoked Potentials;Movement;Nerve Fibers;Nervous System Trauma;Nervous system structure;Neuronal Plasticity;Neurorehabilitation;Outcome;Patients;Performance;Peripheral Nerve Stimulation;Phase;Play;Principal Investigator;Protocols documentation;Recovery;Recovery of Function;Rehabilitation therapy;Research;Residual state;Rewards;Role;Science;Signal Transduction;Speed;Spinal cord injury;Spinal cord injury patients;Synapses;System;Techniques;Testing;Time;Training;Transcranial magnetic stimulation;Volition;acronyms;awake;base;brain machine interface;clinical care;cohort;effective therapy;hand grasp;improved;injured;insight;motor control;motor function recovery;motor learning;motor recovery;novel;post intervention;programs;response;screening;sensory input;theories

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The goal is to develop a brain-machine interface that will detect when a patient with incomplete spinal cord injury attempts hand movement and apply peripheral nerve stimulation (PNS) to send a reward signal to the brain. This is expected to speed up rehabilitation compared to PNS without any effort from the patient.


application_id: 9107249
project_number: 5R01NS079507-06
project_title: Blood-brain barrier function in epilepsy: new targets for therapy
administering_ic: NINDS
award_notice_date: 2016-06-24
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 079507
program_official: KLEIN, BRIAN
project_start_date: 2012-09-30
project_end_date: 2018-11-30
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
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:
DESCRIPTION (provided by applicant): There is a lack in understanding the mechanism responsible for blood-brain barrier dysfunction in epilepsy. This is a significant clinical challene since it prevents development of a therapy to overcome antiepileptic drug (AED) resistance and reduce seizure burden. Our long-term goal is to elucidate the mechanisms that regulate blood-brain barrier function which may lead to new strategies to treat epilepsy and other neuro- logical diseases. The objectives in this application are to identify the mechanism(s) by which seizures trig- ger barrier dysfunction and map key signaling proteins that can potentially serve as targets to repair the blood-brain barrier in epilepsy. Accomplishing these objectives is expected to increase AED brain uptake and reduce seizure burden. Our central hypothesis is that 1) glutamate activates the two-arm LOX/COX pathway thereby decreasing expression and activity of influx transporters and upregulating expression and activity of efflux transporters through the COX arm that 2) glutamate triggers development of barrier leakage through the LOX arm; and that 3) inhibiting cPLA2 to block both arms of the LOX/COX pathway reverses barrier dysfunction and thereby reduces seizure burden. The rationale for this research is that identifying the mechanism(s) responsible for changes in transporter expression and activity and barrier leakage will potentially provide new targets to improve epilepsy treatment and better control seizures. To accomplish the objectives of this application our hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism of seizure-induced changes of transporter expression and activity; 2) Deter- mine the mechanism of seizure-induced blood-brain barrier leakage; and 3) Develop a therapeutic strategy to reduce seizures in chronic epileptic rats. In Aim 1 we will block cPLA2 and COX-2 to reverse seizure-induced changes in transporter expression and activity. We will monitor influx and efflux transporter expression and activity and determine AED brain uptake. In Aim 2 we will inhibit cPLA2 and 5-LOX to map the signaling pathway causing seizure-induced barrier leakage. We will determine expression of tight junction proteins and matrix metalloproteases and assess barrier leakage. In Aim 3 we will evaluate the therapeutic benefit of cPLA2 inhibition on seizure burden in a rat chronic epilepsy model by determining influx and efflux transporter expression and activity assessing barrier leakage and monitoring seizure frequency duration and severity. The proposed research is innovative because it is focused on a new integrated strategy that considers blood-brain barrier transporters as well as barrier leakage and it is designed specifically to repair te barrier to overcome AED resistance and reduce seizures. The proposed research is significant because the expected outcomes will potentially provide a new strategy to improve pharmacotherapy in patients with resistant epilepsy. The proposed research is translational because cPLA2 inhibitors are under development and our strategy has potential to be translated into the clinic.

project_terms:
Antiepileptic Agents;Blood;Blood - brain barrier anatomy;Brain;Chronic;Clinic;Clinical;Data;Development;Disease;Drug resistance;Epilepsy;Extravasation;Frequencies;Functional disorder;Glutamates;Goals;Health;Knowledge;LOX gene;Lead;Leukotrienes;Link;Maps;Matrix Metalloproteinases;Metalloproteases;Mining;Mission;Modeling;Molecular;Monitor;National Institute of Neurological Disorders and Stroke;Outcome;PTGS2 gene;Pathology;Pathway interactions;Patients;Pharmacotherapy;Proteins;Public Health;Rattus;Research;Resistance;Seizures;Severities;Signal Pathway;Signaling Protein;Testing;Therapeutic;Tight Junctions;Translating;United States National Institutes of Health;Up-Regulation;arm;cerebral capillary;design;glutamatergic signaling;improved;inhibitor/antagonist;innovation;nervous system disorder;new therapeutic target;novel strategies;prevent;protein expression;repaired;sis Genes;therapeutic target;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will significantly advance our understanding of blood-brain barrier function in neurological diseases and potentially provide new treatment opportunities for epilepsy. Thus the proposed research is relevant to the mission of the NIH/NINDS which is to develop fundamental knowledge that will help reduce the burden of neurological diseases in people worldwide.


application_id: 9105754
project_number: 5R01HL122676-02
project_title: Cardiovascular Toxicity of Tobacco Products and Constituents
administering_ic: NHLBI
award_notice_date: 2016-04-11
opportunity_number: RFA-OD-13-011
application_type: 5
activity_code: R01
ic: HL
serial_number: 122676
program_official: ITURRIAGA, ERIN
project_start_date: 2015-07-01
project_end_date: 2020-04-30
study_section: Special Emphasis Panel[ZRG1-AARR-J(56)R]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
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:
Acetaldehyde;Acrolein;Address;Adult;Aerosols;Affect;Aldehydes;Animal Model;Animals;Biological Assay;Biological Markers;C57BL/6 Mouse;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chronic Disease;Cigarette;Complex;Complex Mixtures;Cotinine;Creatinine;Data;Disease;Dose;Dyslipidemias;Electronic cigarette;Evaluation;Exposure to;Family Smoking Prevention and Tobacco Control Act;Female;Formaldehyde;Functional disorder;Future;Grant;Guidelines;Health;Human;In Vitro;Individual;Injury;Insulin Resistance;Knowledge;Lead;Lipids;Measures;Mediating;Metabolism;Methods;Modification;Mus;Nicotine;Non-smoker;Organ;Plasma;Policies;Property;Public Health;Risk;Risk Factors;Smoke;Smokeless Tobacco;Smoker;Smoking;System;Thrombosis;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;Validation;Variant;authority;body system;cardiovascular disorder risk;cardiovascular injury;cigarette smoke;cigarette smoking;cohort;disorder risk;environmental tobacco smoke exposure;male;primary outcome;research study;response;secondary outcome;tobacco exposure;urinary


application_id: 9105389
project_number: 5P20GM103436-16
project_title: EKU Lead Faculty Award
administering_ic: NIGMS
award_notice_date: 2016-04-22
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 7046
contact_pi_person_id: 10574352
contact_pi: CALIE, PATRICK JOSEPH
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
budget_start_date: 2016-05-01
budget_end_date: 2017-04-30
project_abstract:
The KBRIN-Centralized Core Facility otherwise known at the Uofl as the Uofl GG enomics Core Facility has been operating as a merged INBRE-COBRE operation since 2008 although certain individual components were available separately from either the INBRE or COBRE awards since 2001. Its objectives are to provide state of the art genomic related technologies including microarray and deep sequencing services to Uofl researchers as well as to investigators in the KBRIN-affiliated institutions and its outreach institutions across the Commonwealth of Kentucky. Its services are centered around the most advanced and comprehensive platforms of high-density oligonucleotide array technologies offered by Affymetrix Inc. and Agilent Inc as well as the next generation sequencing capabilities of the Jon Torrent PGM platform. These platforms allow standardized analyses of RNA or miRNA expression profiles splice patterns and variations DNA mutations and single nucleotide polymorphism profiles. The Facility ensures that all investigators including clinical faculty and basic science groups will be able to adopt such state-of-the-art technologies for their investigative goals using clinical specimen or animal model or cell culture materials.  Since its inception the Facility has experienced a rapid growth in personnel user numbers and diversity of experimental platforms allocated space attendance in training events and resources for data analysis and mining. It has been an integral part of several funded and/or currently pending individual and multi-investigator Center and Training grant applications the strongest case for its longevity and its continued utility. The Facility is currently a key component of COBRE 8P20GM103482-10 Center of Biomedical Research Excellence in Molecular Targets (D. Miller P.l.) COBRE 8P20GM103453-10 Molecular Determinants of Developmental Defects (R. Greene P.l.) NIGMS- KY-INBRE P20GM103436 KY-IDeA Networks of Biomedical Research Excellence award (N. Cooper P.l.) and training grant NIEHS T32 ES11564 Uofl EElnvironmental Health Sciences Training Program (D. Hein P.l.).

project_terms:
Adopted;Animal Model;Applications Grants;Award;Basic Science;Bioinformatics;Biomedical Research;Biometry;Biotechnology;Cell Culture Techniques;Centers of Research Excellence;Clinical;Computer software;Core Facility;DNA;DNA Sequence Alteration;Data Analyses;Data Collection;Defect;Development;Educational workshop;Ensure;Event;Experimental Designs;Faculty;Funding;Gene Expression;Genetic Transcription;Genomic DNA;Genomics;Genotype;Goals;Grant;Health Sciences;Human;Human Resources;Hybridization Array;Individual;Information Sciences;Institution;Internet;Kentucky;Lead;Libraries;Longevity;Manuscripts;Microarray Analysis;Molecular;Molecular Target;Mus;National Institute of Environmental Health Sciences;National Institute of General Medical Sciences;Nursing Faculty;Oligonucleotide Microarrays;Pattern;Preparation;Procedures;Process;Provider;RNA;RNA Splicing;RNA amplification;Research Personnel;Resources;Sample Size;Sampling;Scanning;Schools;Services;Single Nucleotide Polymorphism;Specimen;Technology;Training;Training Programs;Variant;base;data mining;deep sequencing;density;experience;medical schools;miRNA expression profiling;next generation sequencing;operation;outreach;rapid growth;tool;transcriptome


application_id: 9105388
project_number: 5P20GM103436-16
project_title: Genomics Core
administering_ic: NIGMS
award_notice_date: 2016-04-22
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 7045
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
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
budget_start_date: 2016-05-01
budget_end_date: 2017-04-30
project_abstract:
Over a decade ago the development of our bioinformatics infrastructure and capabilities was a new focus for the 2 major research institutions in KY because they had clearly recognizable needs associated with the blossoming of the 'omics' era in the life sciences. More recently health-related and biomedical informatics are seen as challenging necessities for clinical and translational research. The recognition of the importance of bioinformatics is being expressed now in the regional institutions because bioinformatics is seen to be an important requirement in the undergraduate science curriculum especially in biology and computer science classes. We will continue to encourage our KBRIN-affiliated regional institutions to integrate bioinformatics into their research and educational missions. In addition we propose to incorporate our KBRIN-outreach institutions into this 'movement' so that a larger proportion of the state's undergraduate student body can be engaged in our overall integrated genomics/bioinformatics research training/education mission.  Our operational model for bioinformatics (Table 10 above) shows that each of our 6 KBRIN primary networked institutions have resources committed to some aspect of bioinformatics whether it be in research training or education. For example Uofils committed to eliminating the bottlenecks in the data-analyses pipeline that currently hold up progress in research. UK similarly is developing a Clinical Translational Science Award (CTSA) supported bioinformatics center in support of translation/clinical research. A most impressive development in bioinformatics infrastructure among our network has to be the 50 member strong Bioinformatics and Information Science Center (BISC) at WKU. The integration of bioinformatics across departments into a Center-like organization at a regional institution has to be a first. Two faculty members associated with this center have participated for several years in the HHMI's SEA-PHAGE program a unique vehicle for introducing genomics/bioinformatics research training/education to undergraduate students. We intend to make use of their experience and expertise together with the core facilities and resources at the 2 research intensive universities to establish a KBRIN-centric genomics/bioinformatics training exercise in our outreach institutions. This will bring our functional genomics theme to an expanded network of undergraduate students (see administrative core). The bioinformatics core narrative is described under the following headings:   (1) Infrastructure (2) Research (3) Education and Training (4) The Next Five Years. (1) Infrastructure: At Uofl we initially had a major problem building interest and collaborations between interdisciplinary/multi-disciplinary investigators on multiple campuses. These include investigators in Anatomical Science and Neurobiology Biochemistry and. Molecular Biology Bioinformatics and Biostatistics on the Health Sciences campus and Chemistry Computer Engineering and Computer Science Biology Psychology and Mathematics on the main/undergraduate campus geographically separated by several miles. To enhance collaboration between these researchers and engage more biomedical researchers a bioinformatics the PI negotiated with the EVPRI and the Dean oUhe School of Medicine to develop a dedicated 1900 ft2 space and a state-of-the-art videoconferencing facility on the University of Louisville's Health Science Campus (Figure 20) in this past 5 year funding cycle. This space is fully operational and allows for KBRIN to further develop bioinformatics research capability and provide a mechanism for keeping close contact with bioinformatics researchers across campus and throughout the state. It is currently inhabited by KBRIN-affiliated researchers and can accommodate visiting faculty from other campuses and/or KBRIN institutions. We hope to grow this space as additional needs and resources become available.

project_terms:
Anatomy;Biochemistry;Bioinformatics;Biological Sciences;Biology;Biomedical Research;Biometry;Chemistry;Clinical Research;Clinical and Translational Science Awards;Collaborations;Computer software;Computers;Core Facility;Data Analyses;Development;Education;Educational Curriculum;Engineering;Exercise;Faculty;Flowers;Funding;Genomics;Head;Health;Health Sciences;Information Sciences;Institution;Mathematics;Mediation;Mission;Modeling;Molecular Biology;Movement;Neurobiology;Output;Provider;Psychology;Research;Research Infrastructure;Research Personnel;Research Training;Resources;Science;Services;Training;Training and Education;Translational Research;Translations;Universities;Videoconferences;Videoconferencing;Visit;biomedical informatics;computer science;experience;functional genomics;interest;medical schools;member;outreach;programs;undergraduate student


application_id: 9105387
project_number: 5P20GM103436-16
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2016-04-22
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 7043
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
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
budget_start_date: 2016-05-01
budget_end_date: 2017-04-30
project_abstract:
(1) Purpose of the Core: The purpose of the administrative core is to provide sound management of the INBRE-award on behalf of the network and to provide the network with structure direction and leadership to help grow and expand the network to develop ideas - that often originate from network members - into viable projects and to provide logistical support oversight and evaluation functions and also to aid the development of suitable research training and research mentoring activities (Table 3).

project_terms:
Award;Biomedical Research;Development;Evaluation;Health;Leadership;Mentors;Research;Research Infrastructure;Research Training;Structure;Training;Workforce Development;member;sound


application_id: 9105385
project_number: 5P20GM103436-16
project_title: KY IDeA Networks of Biomedical Research Excellence
administering_ic: NIGMS
award_notice_date: 2016-04-22
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
program_official: ARORA, KRISHAN
project_start_date: 2001-09-30
project_end_date: 2019-04-30
study_section: ZGM1-TWD-7(IN)
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
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): The Kentucky INBRE serves a statewide mission to build a sustainable infrastructure with a capacity for biomedical and health-related research and research training. In this application the two research intensive institutions the University of Louisville and the University of Kentucky will partner with our regional comprehensive affiliates including Eastern Kentucky University Morehead State University Northern Kentucky University and Western Kentucky University and with a number of outreach institutions to continue the development of a highly collaborative and successful network. The goal of our network is to build competitive research which will serve as the foundation for excellent training of our students in the biomedical and health-related sciences. We plan to develop and grow our multi-disciplinary research network with an overarching theme of functional genomics. With an emphasis on sustainability we will continue to fund developmental research projects for our junior investigators while providing critical mentoring as well as the requisite infrastructure support for genomics and bioinformatics. Our centralized genomics core facility will provide access to state-of-the-art equipment for microarray and next generation sequencing technologies along with qualified technical support. Similarly we will continue to build a critical mass of expertise and infrastructure in bioinformatics to provide data analysis services for high content and/or high throughput data. We have built undergraduate and graduate training programs in bioinformatics. In the rapidly changing world of biomedical research these facilities and services are essential to providing a pathway to independence for our next generation of investigators. We will provide junior faculty with ail of the tools necessary to become independent investigators thereby building network sustainability and at the same time provide for high quality research training experiences for our students. In summary our strategy is designed to build a sustainable infrastructure with capacity for biomedical and health-related research arid research training. This strategy will aid the development of a highly skilled workforce in the Commonwealth of Kentucky.

project_terms:
Bioinformatics;Biomedical Research;Core Facility;Data;Data Analyses;Development;Equipment;Faculty;Foundations;Funding;Genomics;Goals;Health;Institution;Kentucky;Mentors;Mission;Pathway interactions;Qualifying;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Science;Services;Students;Technology;Time;Training;Training Programs;Universities;design;experience;functional genomics;next generation;next generation sequencing;outreach;programs;research facility;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This INBRE program is designed to build infrastructure and support activities to enhance biomedical research and research training in Kentucky.


application_id: 9104742
project_number: 1R01AA024102-01A1
project_title: The role of dietary unsaturated fat and inflammasome in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2016-07-15
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: AA
serial_number: 024102
suffix: A1
program_official: RADAEVA, SVETLANA
project_start_date: 2016-07-15
project_end_date: 2021-06-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
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
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the world. It affects millions of patients worldwide each year. Although
substantial progress has been made in ALD pathogenesis the specific mechanisms responsible for ALD development and progression remain poorly understood. Importantly there is no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others have demonstrated that dietary unsaturated fat rich in linoleic acid (LA) exacerbated alcohol- mediated intestinal permeability and liver injury as compared with dietary saturated fat in an experimental animal model of ALD. In addition our preliminary data show elevated levels of circulating oxidized LA metabolites (OXLAMs) specifically 9- and 13-hydroxy-octadecadienoic acids (9- and 13-HODEs) concomitant with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) the key enzyme involved in the oxidation of LA. These findings provide initial evidence that OXLAMs which are natural ligands to the transient receptor potential vanilloid 1 (TRPV1 subfamily V member 1) contribute to the pathogenesis of ALD. TRPV1 is a ligand-gated non-selective cation channel with high permeability for Ca2+. A number of recent studies have shown a critical role for intracellular Ca2+ in inflammasome activation. NLRP3 Inflammasome activation with release of highly pro-inflammatory cytokines interleukin-1 (IL-1) and interleukin-18 (IL-18) is an important pro-inflammatory response in ALD. However the molecular mechanisms contributing to the inflammasome priming and activation in ALD are not fully identified.  Our central hypothesis is that dietary unsaturated fat (linoleic acid enriched) exacerbates alcohol-mediated liver inflammation and injury via oxidized linoleic acid metabolites that facilitate hepatic inflammasome activation. We propose that the OXLAM/TRPV1/Ca2+ signaling pathway is an upstream mechanism of inflammasome activation. To address our hypothesis we propose the following specific aims. Aim 1. Determine the role of oxidized linoleic acid metabolites (OXLAMs) and the 12/15-LO-mediated pathway of linoleic acid oxidation in the development and/or progression of ALD.  Aim 2. Assess whether hepatic inflammasome activation is mediated by an OXLAM-TRPV1-Ca2+ pathway in an animal model of ALD.  Aim 3. Determine the potential role of 12/15-LO TRPV1 and OXLAMs in inflammasome activation in human Alcoholic Hepatitis. The proposal will provide a better understanding of alcohol-diet interactions and molecular mechanisms contributing to the pathogenesis of alcohol-induced liver inflammation and injury. The study will lead to identification of new therapeutic targets and potential dietary interventions for treating ALD and
provide a dietary mechanism to explain why only some heavy drinkers develop clinically important ALD.  A combination of in vitro in-vivo animal (gain and loss of function) and human studies will be employed.

project_terms:
Address;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Animals;Arachidonate 15-Lipoxygenase;Attenuated;Binding;Cations;Data;Development;Diet;Dietary Fats;Dietary Intervention;Enzymes;Experimental Animal Model;FDA approved;Fatty Acids;Genetic;Hepatic;Hepatocyte;Human;In Vitro;Inflammatory;Inflammatory Response;Interleukin-1 beta;Interleukin-18;Intestines;Knock-in;Knockout Mice;Kupffer Cells;Laboratories;Lead;Ligands;Linoleic Acids;Mediating;Molecular;Morbidity - disease rate;Mus;Pathogenesis;Pathway interactions;Patients;Permeability;Research;Role;Sampling;Severities;Signal Pathway;Staging;TRPV1 gene;Testing;Transgenic Organisms;United States National Institutes of Health;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;cytokine;in vivo;liver inflammation;liver injury;loss of function;macrophage;member;monocyte;mortality;new therapeutic target;octadecadienoic acid;overexpression;oxidation;peripheral blood;public health relevance;receptor;saturated fat;translational study


application_id: 9103072
project_number: 4K12DA035150-05
project_title: Kentucky BIRCWH Program: Training the Next Generation of Women's Health Scholars
administering_ic: NIDA
award_notice_date: 2016-07-21
opportunity_number: RFA-OD-11-002
application_type: 4
activity_code: K12
ic: DA
serial_number: 035150
program_official: BABECKI, BETH
project_start_date: 2012-08-01
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZRG1-PSE-K(50)R]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
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 University of Kentucky (UK) is uniquely positioned to continue using exceptional and outstanding research infrastructure to train the next generation of women's health scholars. We choose to focus our scholarship efforts on those health challenges unique to Appalachian Kentucky. Because the Appalachian region is disproportionately affected by drug abuse violence and poor health we will actively engage women living in Appalachian Kentucky in our research agenda with research flowing bidirectionally between communities and researchers. This approach will continue to provide our BIRCWH scholars with state-of-the-art multidisciplinary training leading to their development as faculty with independent NIH funding. The focused areas targeted towards improving women's health in this application include: 1) substance abuse 2) violence against women and 3) hormonal regulation across a woman's lifespan. UK is uniquely position to address violence against women because UK has the only US Center focusing on research to prevent violence against women. Through this BIRCWH program strengthening the capacity for women's health research will be accomplished by the following Specific Aims: 1) to provide the environment mentorship and facilities to enhance the ability of BIRCWH scholars to compete for NIH research grants in diverse areas of women's health research 2) to deepen our understanding of the unique role of gender in the manifestation of health and disease 3) to stimulate new collaborations in focused interdisciplinary and interactive research areas that are essential forimproving women's health; and 4) to use a thematic multidisciplinary focus as a platform for enhancing translational research between basic clinical and public health scientists. Key aspects of training will include: (a) pairing the BIRCWH scholar with senior level scientists and former BIRCWH scholars forming a research team and thus modeling interdisciplinary collaboration (b) providing these teams with access to cutting edge technologies and (c) providing scholars with training in concepts relevant to women's health. A strength of our BIRCWH program is its multidisciplinary cross-departmental and interactive nature positioned in an area with unique health needs. As evident by the success of our former BIRCWH scholars we are well positioned to continue the tradition of excellence in mentoring our scholars to become independent researchers in women's health.

project_terms:
Address;Affect;Appalachian Region;Area;Clinical;Collaborations;Communities;Development;Disease;Drug abuse;Environment;Faculty;Funding;Gender Role;Health;Kentucky;Life;Longevity;Mentors;Mentorship;Modeling;Nature;Positioning Attribute;Public Health;Research;Research Infrastructure;Research Personnel;Research Project Grants;Scholarship;Scientist;Substance abuse problem;Technology;Training;Training Programs;Translational Research;United States National Institutes of Health;Universities;Violence;Woman;Women's Health;hormone regulation;improved;interdisciplinary collaboration;multidisciplinary;next generation;programs;success;violence against women;violence prevention

public_health_relevance:
Emphasizing gender differences in effective health care research and treatment is critical. We must train the next generation of scientists to recognize and apply these differences. This proposal will provide a platform to mentor and train promising young scientists in focused areas of women's health research to address the unique needs in women's health especially for those who are underserved.


application_id: 9103064
project_number: 5R21DA038817-02
project_title: Single molecule determination of nAChR structural assembly for therapeutic targeting
administering_ic: NIDA
award_notice_date: 2016-06-23
opportunity_number: PAR-13-350
application_type: 5
activity_code: R21
ic: DA
serial_number: 038817
program_official: HILLERY, PAUL
project_start_date: 2015-07-01
project_end_date: 2017-06-30
study_section: Biophysics of Neural Systems Study Section[BPNS]
contact_pi_person_id: 8957529
contact_pi: RICHARDS, CHRISTOPHER I
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:
DESCRIPTION (provided by applicant): The consumption of tobacco products leads to the elevation of several health risks. Smokers have a higher likelihood of developing cardiovascular disease respiratory disease and several types of cancer. As a result approximately 20% of all deaths in the United States are associated with tobacco products. Despite the clear hazards it is estimated that more than 40 million adults in the United States are smokers. One of the primary barriers to decreasing the number of smokers is that nicotine a component of tobacco is highly addictive. We propose a novel approach to elucidate the mechanism of nicotine addiction and to identify target nAChR assemblies and phenotypes for nicotine cessation therapeutics. In the R21 phase we will focus on the development of a novel approach to monitor the assembly and trafficking of nicotinic receptors at the single molecule level. Nicotinicreceptors cannot be purified outside of the cellular environment making them inaccessible to common single molecule techniques that require the purification and reconstitution of proteins. We will utilize receptors isolated in cell derived vesicles. Isolation of vesicles from different organelles will allow us to determine nicotine and therapeutic ligands affect the assembly and trafficking of nAChRs. Identification of the specific structural assemblies targeted by existing therapeutics will allow us to identify specific targets for cessation therapeutics. In the R33 phase we will extend studies to receptors generated in live animals by isolating vesicles from different regions of the brain of nicotinic receptor GFP knock-mice. These will be the first singlemolecule studies of nicotinic receptors generated in live animals. We will be able to correlate theassembly of different receptor subtypes to specific brain regions. These studies will for the firsttime allow us to perform single molecule fluorescence studies on brain derived nAChRs. Understanding how existing therapeutics alter structural assembly in specific brain regions will provide an understanding of which nAChRs to target and the structural assembly they should induce. This will provide insight into the mechanism of nicotine addiction and on the receptor phenotypes optimally induced by cessation therapeutics.

project_terms:
Adult;Affect;Animals;Brain;Brain imaging;Brain region;Cardiovascular Diseases;Cell membrane;Cells;Cessation of life;Development;Environment;Exposure to;Fluorescence;Goals;Golgi Apparatus;Health;Image;Knock-in Mouse;Label;Life;Ligands;Lung diseases;Measures;Mediating;Membrane;Molecular Chaperones;Monitor;Mus;Nicotine;Nicotine Dependence;Nicotinic Receptors;Organelles;Phase;Phenotype;Play;Risk;Role;Series;Smoker;Sorting - Cell Movement;Structure;Synapses;Synaptosomes;Techniques;Testing;Therapeutic;Therapeutic Effect;Time;Tobacco;Tobacco use;United States;Vesicle;addiction;cancer type;fluorescence imaging;hazard;in vivo;innovation;insight;novel;novel strategies;novel therapeutics;presynaptic;protein reconstitution;receptor;research study;single molecule;stoichiometry;targeted treatment;therapeutic target;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The consumption of tobacco products leads to a higher likelihood of developing cardiovascular disease respiratory disease and several types of cancer. Despite the clear hazards it is estimated that more than 40 million adults in the United States are smokers. The proposed studies will help to elucidate the underlying mechanism of nicotine addiction and will identify specific structural targets for therapeutic targeting.


application_id: 9102243
project_number: 4R25GM102776-05
project_title: Kentucky Bridge to a Biomedical Doctorate for Appalachian Students
administering_ic: NIGMS
award_notice_date: 2016-06-16
opportunity_number: PAR-11-279
application_type: 4
activity_code: R25
ic: GM
serial_number: 102776
program_official: BROWN, PATRICK
project_start_date: 2012-09-01
project_end_date: 2018-08-31
study_section: Minority Programs Review Subcommittee A[MPRC-A]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
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): This Bridges to Doctorate Program is an initiative by faculty at Eastern Kentucky University (EKU) and the University of Kentucky (UK) to prepare underrepresented students for careers in biomedical research. The primary target student population for this Bridges grant will be those from Appalachian counties considered to be "distressed" or "at-risk" due to their significant unemployment and poverty rates. The rationale tofocus on distressed Appalachian counties is that they comprise a large part of the EKU service region although this Bridges program will also endeavor to recruit students from other underrepresented groups. EKU and UK are ideal partners for this particular Bridges program; both are geographically situated close to the region targeted in this grant a strong relationship already exists between these two institutions and their proximity will allow Bridge students to travel easily from EKU to UK for symposia and classes. A comprehensive plan is proposed to provide strong masters level training to Bridge students while at EKU to prepare them to transition to the UK Integrated Biomedical Sciences (IBS) program where they will pursue doctoral studies in biomedical research. The aims of this proposal are to: (1) recruit talented Appalachian students to a comprehensive interdisciplinary master's program to EKU with mentoring from EKU and UK faculty (2) provide Appalachian Bridge students with the skill sets needed for continued training at the PhD level including an intensive research experience that requires a written research proposal and thesis workshops courses and seminars (3) provide opportunities to showcase the achievements of Appalachian Bridge students at local regional and national meetings and (4) develop a series of metrics to rigorously evaluate the success of the EKU-UK Bridges to Doctorate program and make adjustments/improvements when warranted. With an excellent group of faculty from EKU and UK who have agreed to serve as mentors for this program we anticipate the ability to recruit 5 students/year to this 2-year master's program.

project_terms:
Achievement;Address;Admission activity;Appalachian Region;Attention;Award;Bachelor's Degree;Biomedical Research;Books;Country;County;Data;Data Reporting;Degree Completion;Degree program;Disadvantaged;Distress;Doctor of Philosophy;Doctor's Degree;Educational Background;Educational Curriculum;Educational Status;Educational workshop;Ensure;Ethics;Evaluation;Faculty;Financial Support;Goals;Grant;Institution;Joints;Kentucky;Lead;Life;Master's Degree;Measures;Mentors;Methods;Online Systems;Oral;Peer Review;Population;Poverty;Preparation;Publications;Recruitment Activity;Research;Research Proposals;Resources;Rest;Risk;Schools;Science;Scientist;Series;Services;Students;Training;Travel;Underrepresented Groups;Underrepresented Populations;Underrepresented Students;Unemployment;Universities;Work;Writing;abstracting;base;bridge program;bridge to the doctorate;career;college;experience;higher education;improved;meetings;news;programs;skills;sobriety;success;symposium;undergraduate education

public_health_relevance:
The goal of this Bridges to Doctorate program is to prepare underrepresented baccalaureate students with master level training at Eastern Kentucky University in preparation for transition to the Integrated Biomedical Sciences PhD program at the University of Kentucky. This Bridges program will primarily target students from Appalachia a disadvantaged region that is already a large part of the Eastern Kentucky University service region. The aims of this grant will provide comprehensive research-intensive training and includes an evaluation plan to insure that the program is achieving its stated objectives.


application_id: 9101334
project_number: 1R21CA205778-01
administering_ic: NCI
award_notice_date: 2016-03-19
opportunity_number: PAR-13-146
application_type: 1
activity_code: R21
ic: CA
serial_number: 205778
program_official: LI, JERRY
project_start_date: 2016-08-01
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZCA1 SRB-X (J1)]
contact_pi_person_id: 10631406
contact_pi: WANG, CHI
other_pis: MOSELEY, HUNTER NATHANIEL
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
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
budget_start_date: 2016-08-01
project_title:
Statistical Detection and Biochemical Classification of Cancer Driver Mutation Patterns in Biological Networks

project_abstract:
DESCRIPTION (provided by applicant): Cancer arises from somatically acquired genetic and epigenetic alterations. While large consortia like The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) have profiled genomic somatic mutations of thousands of tumor samples from various cancer types based on whole-genome/exome sequencing meaningful mechanistic interpretation of these gene variation results are still very limited. One basic yet challenging task is to distinguish driver mutations which are causally implicated in cancer development from passenger mutations which occur randomly with neutral effect. Another critical task is to map trace and interpret the functional impact of drivr mutations within biological networks. In a network context driver mutations associated with genes within a pathway often show a mutually exclusive pattern meaning that each patient carries exactly one mutation in the pathway which is sufficient to perturb the function of that pathway. Another prominent pattern is that driver mutations of genes from several different pathways may co-occur since perturbation of multiple pathways is required for tumor formation. Screening for mutual exclusivity and co-occurrence patterns can greatly facilitate the identification of novel sets of related driver gene mutations their associated driver pathways and functional relationships between these driver pathways. Although several de novo driver mutation gene set discovery methods have been proposed in the past few years they have major limitations due to computational feasibility an inability to deal with mutational heterogeneity across patients and lack of biochemical interpretation.  The overall goal of this proposal is to develop and combine advance sequence variation analyses with complementary biological network analyses into a highly novel systems biology approach that will: i) detect sets of related mutations in driver regulatory/signaling pathways ii) classify these pathways as stimulated inhibited or mixed with respect to their role in the tumor development process and iii) predict direct metabolic outcomes of these perturbed pathways. Our specific aims are: 1) to develop a statistical method for de novo discovery of mutually exclusive and co-occurrent sets of driver mutations; and 2) to develop a pathway mapping and classification method for related sets of driver mutations. The identification and biochemical interpretation of aggregated tumor mutations from driver mutation gene sets to inhibited/stimulated pathways to perturbed biological network will provide new mechanistic insights in tumor progression at a systems level. Also with this information potential drug targets in the detected driver pathways can be classified as requiring agonist or antagonist drug development making drug target evaluation and prioritization much more effective. Furthermore identification of co-occurrence between specific genes and pathways may aid in the development of multi- therapeutic cancer treatments that are optimized to groups of patients showing the same mutational patterns of co-occurrence.

project_terms:
Accounting;Agonist;Biochemical;Biological;Classification;Computing Methodologies;Data;Detection;Development;Drug Targeting;Effectiveness;Epigenetic Process;Evaluation;Gene Mutation;Genes;Genetic;Goals;Heterogeneity;Human;Individual;International;Knowledge;Malignant Neoplasms;Maps;Markov chain Monte Carlo methodology;Metabolic;Methods;Mutate;Mutation;Outcome;Pathway interactions;Patients;Pattern;Process;Role;Sampling;Signal Pathway;Somatic Mutation;Statistical Methods;System;Systems Biology;Testing;The Cancer Genome Atlas;Therapeutic;Variant;actionable mutation;antitumor drug;base;biological systems;cancer classification;cancer genome;cancer therapy;cancer type;drug development;exome sequencing;genome-wide analysis;genomic profiles;innovation;insight;interest;novel;public health relevance;screening;success;tool;tumor;tumor progression;whole genome

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The objective of this proposed project is to develop statistical and systems biology methods to identify classify and interpret sets of somatically mutated genes that drive cancer development. The success of this project will provide new mechanistic insights in tumor progression at a systems level and enhance the effectiveness of antitumor drug target evaluation and prioritization.


application_id: 9100732
project_number: 5R21ES023627-02
project_title: Differential miRNA expression & progression of arsenic induced skin cancers
administering_ic: NIEHS
award_notice_date: 2016-06-21
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: ES
serial_number: 023627
program_official: HUMBLE, MICHAEL C
project_start_date: 2015-07-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-SIEE-C(01)Q]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
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): Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are two types of skin cancer caused by both sunlight and arsenic exposure. It is clear that mutations from UV-induced DNA damage drive sunlight induced skin cancers. In contrast the mechanism of arsenic induced skin cancer remains unclear. This exploratory project will characterize the differential microRNA expression in primary human keratinocytes exposed long term to arsenic in vitro and in a unique sample set of arsenic induced skin lesions including hyperkeratosis (premalignant lesion to both arsenic induced BCC and SCC) BCC and SCC. MicroRNA expression profiles will be determined by microarray analyses of RNA purified from primary human keratinocytes exposed and unexposed to arsenite in vitro and in laser capture microdissection purified keratinocytes from formalin fixed paraffin embedded samples of the arsenic induced skin lesions. Differential microRNA expression for the 6 microRNAs with greatest fold change between comparison sets will be confirmed by qRT-PCR. Comparisons between exposed and unexposed primary human keratinocytes will identify arsenic exposure induced changes in microRNA expression that may contribute to cellular transformation. Comparisons between HK vs BCC and HK vs SCC will reveal changes associated with progression from pre-malignant to malignant phenotype and between BCC vs SCC will reveal similarities and dissimilarities between the two tumor types. Comparison of the microRNA expression profiles unique to arsenic induced BCC and SCC with the published data from sunlight induced BCC and SCC will provide critical molecular information on the similarity or dissimilarity of these phenotypically similar cancers induced by different environmental carcinogens. Completion of these studies will provide novel data on arsenic induced changes in microRNAs in primary human keratinocytes and in progression of arsenic induced skin cancers. Extension of these studies in the future using multiple lesions from single individuals and by combining data with mRNA expression profiles will provide detailed molecular information on tumor progression.

project_terms:
Affect;Arsenic;Arsenites;Basal cell carcinoma;Biological Assay;Biological Markers;Cancer Etiology;Chronic;Country;DNA Damage;Data;Development;Disease;Environmental Carcinogens;Epigenetic Process;Etiology;Exposure to;Female;Formalin;Future;Gene Expression;Gene Expression Profile;Health;Human;Hyperkeratosis;In Vitro;Incubated;Individual;Induced Mutation;Lesion;Light;Malignant - descriptor;Malignant Neoplasms;Messenger RNA;MicroRNAs;Microarray Analysis;Molecular;Molecular Profiling;Mutagenesis;Mutation;Outcome;Paraffin Embedding;Pattern;Premalignant;Principal Component Analysis;Publishing;RNA;Role;Sampling;Skin Cancer;Skin Carcinogenesis;Squamous cell carcinoma;Sunlight;TP53 gene;Testing;Tissues;UV induced;arsenic-induced carcinogenesis;contaminated drinking water;differential expression;drinking water;driving force;gender difference;keratinocyte;laser capture microdissection;mRNA Expression;male;malignant phenotype;melanoma;metaplastic cell transformation;molecular phenotype;novel;skin lesion;sunlight-induced;tumor;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Arsenic exposure in drinking water is a worldwide health problem affecting numerous countries including the U.S. A common outcome of chronic arsenic exposure is skin cancer. This project will provide information on the molecular mechanisms of skin cancer development in arsenic exposed individuals using a unique set of samples of premalignant and malignant lesions from people chronically exposed to arsenic in their drinking water.


application_id: 9100693
project_number: 5R01DA036550-03
project_title: Human Laboratory Screening of Pregabalin and Tiagabine for Cannabis Dependence
administering_ic: NIDA
award_notice_date: 2017-06-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 036550
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-01
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
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): Cannabis use disorders are a significant public health concern and the absence of effective medications is a critical barrier to overcome. This application is founded on promising results from our laboratory suggesting that drugs that act at a2d-1 subunit containing voltage-dependent calcium channels (VDCCs) and/or elevate g- aminobutyric acid (i.e. GABA) will be effective medications for cannabis-use disorders. Our laboratory results are supported by a recent pilot clinical trial showing that gabapentin which isa VDCC ligand and elevates GABA reduced cannabis use in dependent treatment-seeking adults. The goal of the present proposal is to build upon these promising laboratory and clinical findings by determining the ability of outpatient maintenance on pregabalin a "next generation" VDCC ligand and tiagabine a GABA reuptake inhibitor to attenuate the reinforcing effects of cannabis. Pregabalin will be tested because although their mechanism of action is the same the pharmacokinetic profile of pregabalin is improved compared to gabapentin and clinical results suggest that this translates into greater pharmacotherapeutic effectiveness. Tiagabine will be tested because its effects overlap with gabapentin and pregabalin GABA elevation is a possible mechanism for gabapentin's effects on cannabis use and our recent data demonstrated that tiagabine produced a profile of effects that was comparable to gabapentin when tested in combination with D9-THC. Outpatient maintenance dosing will be tested because it more closely resembles the clinical treatment situation. Cannabis self-administration using a concurrent progressive-ratio drug-money choice procedure will be the primary outcome because drug seeking and drug taking behaviors and the choice to use drugs to the exclusion of other behaviors are defining characteristics of drug dependence and drug self-administration procedures are predictive of therapeutic efficacy. Cannabis use in the natural environment will also be monitored during drug maintenance as a secondary outcome to optimize resource management and quicken the pace of intervention development. Our preliminary data with the proposed procedures support the feasibility of the project the assembled research team is highly qualified and the environment will significantly contribute to the success of the research. The proposed project is innovative because it employs a novel hybrid procedure to study the impact of medication maintenance on direct cannabis effects in the laboratory as well as cannabis use in the natural environment the effects of pregabalin and tiagabine on cannabis self-administration have not been tested previously and a novel real-time medication maintenance compliance technology will be implemented. Positive findings will exert an immediate and sustained impact by rapidly advancing currently available medications for the treatment of cannabis-use disorders promoting novel pharmacological targets for further medications development and providing valuable basic science information about the mechanisms underlying cannabis reinforcement.

project_terms:
Abstinence;Acute;Admission activity;Adult;Adverse effects;Attenuated;Award;Basic Science;Behavior;Behavior Therapy;Calcium Channel;Cannabis;Characteristics;Clinical;Clinical Treatment;Clinical Trials;Cost Savings;Data;Dependence;Development;Dose;Double-Blind Method;Drug Addiction;Drug Kinetics;Drug usage;Effectiveness;Environment;Exclusion;Goals;Human;Hybrids;Illicit Drugs;Incentives;Independent Scientist Award;Information Sciences;Intervention;Laboratories;Ligands;Maintenance;Marijuana Dependence;Measures;Methods;Modeling;Monitor;Motivation;Outpatients;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Placebo Control;Principal Investigator;Procedures;Process;Psychological reinforcement;Public Health;Randomized;Relapse;Research;Resources;Role;Schedule;Self Administration;Statistical Data Interpretation;Statistical Models;Study Subject;Techniques;Technology;Testing;Therapeutic Effect;Time;Translating;Treatment Efficacy;United States;career development;cost effectiveness;drug maintenance;experience;gabapentin;gamma-Aminobutyric Acid;illicit drug use;improved;inhibitor/antagonist;innovation;marijuana use;marijuana use disorder;marijuana user;next generation;novel;pregabalin;primary outcome;public health relevance;reinforcer;response;reuptake;screening;secondary outcome;success;therapy development;tiagabine;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs that are often perceived as more harmful. Currently there are no effective pharmacological treatments for cannabis-use disorders. This project will evaluate pregabalin and tiagabine for cannabis-use disorders using state-of-the-art human laboratory methods.


application_id: 9100670
project_number: 5R01DA036827-03
project_title: Topiramate-Phentermine Combinations for Cocaine Dependence
administering_ic: NIDA
award_notice_date: 2017-03-21
opportunity_number: PA-10-268
application_type: 5
activity_code: R01
ic: DA
serial_number: 036827
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-15
project_end_date: 2019-09-30
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): Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are needed to identify an effective pharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiological substrates with drug dependence for example could yield treatments for managing COC dependence. Obesity is also a significant public health concern. While obesity and COC dependence are typically considered distinct clinical entities both involve perturbations of central biogenic amie systems. The obesity epidemic has spurred development of medications to promote weight loss. The Food and Drug Administration (FDA) recently approved a combination of topiramate (TOP) and phentermine (PHEN) for obesity. The overarching goal of this application is to demonstrate the initial efficacy safety and tolerability of TOP-PHEN combinations for COC dependence. A mixed-model experiment will be conducted in which separate cohorts of non-treatment-seeking COC-dependent participants will be randomized to different TOP maintenance doses (i.e. TOP is a between-subject factor). Participants (N=12) in each TOP cohort will be maintained concurrently on PHEN (i.e. PHEN is a within-subject factor). The reinforcing effects of COC will be determined after participants in each TOP cohort are maintained for 7 days on each PHEN dose (i.e. COC is a within-subject factor). COC (4 [placebo] 40 80 mg) will be tested with each dose combination of TOP (0 100 200 mg/day) and PHEN (0 15 30 mg/day). The proposed study will therefore identify the optimal TOP-PHEN dose combination that most effectively attenuates the reinforcing effects of COC. This research will provide critical information regarding the initial efficacy and optimal doses of a novel drug combination TOP and PHEN for COC dependence which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposal include: 1) testing a drug combination effective for a disorderobesity that shares neurobiological and behavioral substrates with COC addiction; 2) the use of drug self-administration procedures; 3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of TOP-PHEN combinations for COC addiction; 4) demonstrating the initial efficacy of commercially available drugs as opposed to waiting for novel molecules to be available for testing in humans thereby impacting clinical research and practice more quickly; 5) facilitating communications between scientists studying distinct clinicalentities (e.g. obesity and COC addiction); and 6) spurring sponsor interest in addiction pharmacotherapy because demonstrating the efficacy of the TOP-PHEN combination would support a novel indication for this product in a new population and extend patent life. The proposed project will shift the current research paradigm in pharmacotherapy development and have a significant impact on COC abuse treatment.

project_terms:
Abstinence;Adverse effects;Attenuated;Behavior Therapy;Behavioral;Biogenic Amines;Body Weight;Body Weight decreased;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Communication;Development;Disease;Dose;Drug Addiction;Drug Combinations;Drug usage;Enrollment;Epidemic;Excitatory Amino Acid Antagonists;Food;GABA Agonists;Goals;Human;Inpatients;Investigation;Laboratory Study;Legal patent;Life;Maintenance;Medication Management;Modeling;Mono-S;Neurobiology;Obesity;Outcome Measure;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Phentermine;Physiological;Placebos;Population;Probability;Procedures;Public Health;Questionnaires;Randomized;Research;Research Design;Safety;Scientist;Self Administration;System;Testing;United States Food and Drug Administration;Work;addiction;clinical practice;cocaine use;cohort;double-blind placebo controlled trial;experimental study;indexing;innovation;interest;monoamine;novel;novel drug combination;programs;public health relevance;reinforcer;secondary outcome;success;topiramate

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 topiramate and phentermine 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 topiramate-phentermine combinations for managing cocaine dependence.


application_id: 9100598
project_number: 4R01AG046116-04
project_title: Pain and Well-being in Older Women: The Roles of Activity and Motivation
administering_ic: NIA
award_notice_date: 2016-03-21
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: AG
serial_number: 046116
program_official: NIELSEN, LISBETH
project_start_date: 2013-07-01
project_end_date: 2018-03-31
study_section: Special Emphasis Panel[ZRG1-BBBP-T(03)M]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
other_pis: CROFFORD, LESLIE J
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): The prevalence of chronic pain in older adults is high and prevalence increases with increasing age. Although adverse effects of pain on hedonic well-being (HWB) are well documented there is less evidence that pain has a direct effect on aspects of eudaemonic well-being (EWB) such as autonomy and social satisfaction. Evidence suggests that some older adults with high physical pain nonetheless maintain high EWB whereas others with low physical pain have low EWB. The present study tests a model in which qualities of the goal-directed and physical activities of older women determine whether and how pain affects EWB. When activity is externally motivated by guilt or control pain will inhibit activity and activity will adversely affect EWB; when activity is autonomously motivated by interest or self-definition pain will not inhibit activity and activity will enhance EWB. Furthermore when activities are accorded more time these effects will be stronger. A second aim tests effects of activity and EWB on biomarkers including diurnal cortisol and inflammation as measured by interleukin-6 and its soluble receptor. A third aim will test these relationships controlling for individual differences in personality genotype fitness and pain sensitivity. Oldr women (N = 300 aged 50-75) with varying levels of pain will be recruited from an existing registry to complete 7-day diary periods at 3-month intervals over 9 waves to test day- wave- and person-level relationships. Daily measures will include goal-directed and physical activities (including motivation for and time spent in the activities) cortisol slope subjective health pai pain interference HWB and psychological need satisfaction as a measure of day-level EWB. Wave-level measures will include the Scales of Psychological Well-Being HWB interleukin-6 and interleukin-6 receptor. Person-level measures will include optimism COMT polymorphism VO2max and sensory testing. Multi-level modeling will test for between-person and within-person relationships and lagged effects. The co-PIs bring expertise in pain goals well-being and physiology to these aims and have successfully completed longitudinal studies of older adults and pain patients including a diary study. The study will advance understanding of how a common age-relevant experience - physical pain - affects EWB and physical health.

project_terms:
Adverse effects;Affect;Age;Aging;Area;Arthritis;Back Pain;Biological Markers;Elderly;Feeling;Female;Genetic Polymorphism;Genotype;Goals;Guilt;Headache;Health;High Prevalence;Hydrocortisone;Individual;Individual Differences;Inflammation;Interleukin 6 Receptor;Interleukin-6;Link;Literature;Longitudinal Studies;Measures;Modeling;Moods;Motivation;Musculoskeletal Pain;Neurosecretory Systems;Outcome;Pain;Pain interference;Pain management;Patients;Personal Satisfaction;Personality;Persons;Physical activity;Physiological;Physiology;Prevalence;Prevalence Study;Recruitment Activity;Registries;Reporting;Role;Sensory;Severities;Testing;Time;VO2max;Woman;aged;chronic pain;diaries;experience;fitness;heart rate variability;hedonic;improved;interest;negative affect;older women;optimism;physical conditioning;prognostic;psychologic;psychosocial;receptor;resilience;satisfaction;sex;social

public_health_relevance:
PUBLIC HEALTH RELEVANCE: As people age they are more likely to experience physical pain. However some older adults are able to maintain high feelings of well-being about themselves and their lives despite pain whereas some do not maintain well-being although they have little pain. This study tests whether daily activities determine whether pain does or does not result in decrements in well-being and whether activity and well-being affect immunological and neuroendocrine correlates of health.


application_id: 9099846
project_number: 4R01EY021769-05
project_title: The role of Insm1a in photoreceptor differentiation
administering_ic: NEI
award_notice_date: 2016-06-28
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: EY
serial_number: 021769
program_official: NEUHOLD, LISA
project_start_date: 2012-08-01
project_end_date: 2018-07-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
other_pis: Not Applicable
congressional_district: 06
department: 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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Retinitis pigmentosa (RP) and allied inherited retinal dystrophies are a leading cause of blindness for which there is currently no cure. One potential treatment for retinal degenerative diseases is cell-based transplantation therapy whereby progenitor cells are transplanted into the diseased eye to replace the lost photoreceptors. While this is an exciting possibility several challenges to the implementation of transplantation therapies must be overcome including the inefficient integration of retinal progenitor cells (RPCs) into the recipient retina and the difficulty of obtaining sufficient numbers of photoreceptor precursors for clinical application. Protocols for the in vitro culture of RPCs must be developed that will produce large numbers of photoreceptor precursors and will promote their survival and differentiation once transplanted. Defining the transcriptional networks that promote specification of photoreceptor precursors is a necessary next step for the evolution of therapeutic strategies. One of the long-term goals of our laboratory is to contribute to these efforts by studying photoreceptor development and regeneration in the zebrafish. The zebrafish is especially useful for studying photoreceptor biology because its retina contains numerous cone subtypes in addition to rods. Furthermore unlike mammals the zebrafish retina is able to regenerate neurons in response to experimental damage. We have recently identified the transcriptional repressor Insm1a as a candidate regulator of photoreceptor differentiation and regeneration. The experiments described in this proposal will define the role of Insm1a during retinal neurogenesis through the application of genetic and molecular genetics approaches. Our specific aims are as follows: Specific Aim I: Determine the role of Insm1a in regulating photoreceptor differentiation during retinal development at the cellular level using both loss- and gain-of-function experiments to place Insm1 within the genetic hierarchy of known photoreceptor development genes and to determine whether it is required for retinal progenitor cell cycle exit; Specific Aim II: Identify the molecular targets of Insm1 regulation in the retinausing a combination of gene expression profiling digital gene expression analysis in vitro reporter assays and in vivo chromatin immunoprecipitation. Completion of our proposal will bridge important gaps in our understanding of the molecular mechanisms of vertebrate photoreceptor differentiation and reveal underlying principles relevant to the development of approaches for the effective treatment of human retinal disease.

project_terms:
Address;Adoption;Ally;Animal Model;Animals;Biological Assay;Biology;Blindness;Cell Cycle;Cell Cycle Progression;Cell Survival;Cell Transplants;Cells;Cone;Data;Development;Disease;Embryo;Evolution;Eye;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Gene Targeting;Genes;Genetic;Goals;Human;Immunohistochemistry;In Situ Hybridization;In Vitro;Inherited;Injury;Investigation;Laboratories;Luciferases;Mammals;Methods;Modeling;Molecular;Molecular Genetics;Molecular Target;Mus;Mutation;Natural regeneration;Nerve Regeneration;Neurons;Pathway interactions;Photoreceptors;Population;Protocols documentation;Regulation;Reporter;Retina;Retinal;Retinal Degeneration;Retinal Diseases;Retinal Dystrophy;Retinitis Pigmentosa;Role;Staging;Stem cells;System;Therapeutic;Transcription Repressor/Corepressor;Transplantation;Vertebrate Photoreceptors;Visual impairment;Zebrafish;Zinc Fingers;base;blastocyst;cell type;chromatin immunoprecipitation;clinical application;digital;effective therapy;gain of function;gene therapy;genetic approach;in vivo;neurogenesis;photoreceptor degeneration;promoter;research study;response;retinal neuron;retinal progenitor cell;retinal rods;retinogenesis;stem;therapy development;transcription factor

public_health_relevance:
The development of therapies to treat visual impairment resulting from photoreceptor degeneration will directly benefit from studies of animal models such as the zebrafish which develops ex utero remains optically transparent throughout development and which displays the capacity for injury-induced neural regeneration. The goal of our proposal is to define the role of a transcriptional regulator Insm1 in the development of photoreceptor cells and to identify the genes that are controlled by Insm1 in the developing retina. This information will facilitate efforts to guide photoreceptor differentiation from stem clls in vitro and in vivo for therapeutic purposes.


application_id: 9099819
project_number: 5R01DE014605-14
project_title: Inter-kingdom signaling by A. actinomycetemcomitans
administering_ic: NIDCR
award_notice_date: 2016-07-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DE
serial_number: 014605
program_official: LUNSFORD, DWAYNE
project_start_date: 2003-02-01
project_end_date: 2019-07-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
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): Periodontitis  is  a  widespread  and  costly  disease  that  is  primarily  manifest  in  the  oral  cavity  but  is  also  associated  with  systemic  dieases  such  as  atherosclerosis  and  rheumatoid  arthritis.    Although  several  organisms  have  been identified  as  periodontal  pathogens  A. actinomycetemcomitans has  been  strongly  associated with aggressive forms of periodontitis.  Our prior work showed that quorum sensing is essential for A.  actinomycetemcomitans  virulence  and  we  identified  the  QseBC  two  component  system  as  a  critical  component  of  the  quorum  sensing  pathway.    Our  new  results  suggest  that  QseBC  may  interact  with  catecholamine hormones produced by the host and thus QseBC may mediate both cell density dependent  signaling and inter-kingdom signaling.  This application focuses on the mechanisms of interaction of the two  component  system  with  catecholamine  hormones  and  is  potential  role  in  regulating  iron  uptake  by  A. actinomycetemcomitans.  Aim 1 will determine if catecholamine hormones and iron represent signals that activate QseBC and identify functional motifs of the QseC sensor that are required for binding.  The genes  that  are  regulated  upon  activation  of  QseBC  will  also  be  identifed  using  genomic  microarrays.  Aim 2 will study an operon encoding a putative enterobactin receptor and transporter and determine if this receptor interacts with catecholamine-iron complexes.    The  contribution  of  the  enterobactin  receptor  to  virulence  will  also be examined  using  a  mouse  model  of  periodontitis.    We have also shown that QseBC may be coupled to the cell stress response through the activity of two iron responsive toxin-antitoxin (TA) systems. This regulatory  network  will  be  studied  in  Aim  3  to  determine  if  the  expression  of  stress  proteases  is  induced under iron limiting conditions and whether these proteases activate the TA toxins by degrading the  labile  antitoxin.    The  effect  of  TA  toxin activation  on  the  expression  of  QseBC  and  virulence  of  A. actinomycetemcomitans will also be determined.  The overall goal of this study is to better understand the functional outcomes of activation of the essential QseBC two component system and how signaling through QseBC contributes to virulence.

project_terms:
ATP-Binding Cassette Transporters;Actinobacillus actinomycetemcomitans;Address;Adult;Antitoxins;Atherosclerosis;Bacterial Proteins;Binding;Binding Proteins;Bordetella;Catecholamines;Cell Density;Cells;Cellular Stress;Cellular Stress Response;Complex;Coupled;Data;Disease;Enterobactin;Environment;Expenditure;Family;Funding;Genes;Genome;Genomics;Gingival Pocket;Goals;Growth;Health;Heart Diseases;Hormones;Infection;Inflammatory;Iron;Lactoferrin;Ligands;Mediating;Microbial Biofilms;Mouth Diseases;Operon;Oral cavity;Organism;Orphan;Pathway interactions;Peptide Hydrolases;Periodontitis;Phagocytes;Phenotype;Population;Prevention;Production;Proteins;Regulation;Regulon;Rheumatoid Arthritis;Role;Siderophores;Signal Transduction;Stimulus;Stress;System;Testing;Toxin;Transferrin;United States;Virulence;Work;biological adaptation to stress;deprivation;functional outcomes;macrophage;mouse model;mutant;neutrophil;pathogen;periplasm;prevent;quorum sensing;receptor;response;sensor;solute;targeted treatment;therapeutic target;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Periodontitis  is  a  common  oral  disease  that  is  present  in  up  to  40%  of  the  adult  population  in  the  United  States. Annual expenditures for treatmentand prevention of periodontitis exceed $15 billion.  Although periodontitis is primarily manifest i the oral cavity it is also  associated  with  systemic illnesses  such as heart disease and rheumatoid  arthritis. Our recent studies suggest that the periodontal pathogen A. actinomycetemcomitans  interacts  with  host  hormones  and  iron  and  that  this  interaction  contributes  to  its  virulence.  This study will characterize the bacterial proteins that are invoved in this interaction in order to understand their role in disease.  These proteins represent new potential targets for therapies that may control or prevent periodontitis and the systemic illnesses associated with this disease.


application_id: 9099815
project_number: 5K01CA197073-02
project_title: Intestinal phosphatidylcholine exposure and breast cancer risk
administering_ic: NCI
award_notice_date: 2016-06-16
opportunity_number: PAR-12-050
application_type: 5
activity_code: K01
ic: CA
serial_number: 197073
program_official: SOYOMBO-SHOOLA, ABIGAIL ADEBISI
project_start_date: 2015-07-01
project_end_date: 2020-06-30
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 10392720
contact_pi: ONONO, FREDRICK ONYANGO
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adipose tissue;Animals;Attenuated;Award;Bile fluid;Bioavailable;Blood;Blood Circulation;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast cancer metastasis;Calories;Cancer Patient;Cancer Prognosis;Chylomicrons;Clinical;Consumption;Data;Diet;Dietary Fats;Disease;Enterocytes;Enzymes;Exposure to;Fasting;Fatty acid glycerol esters;Food;Funding;Future;Genetic;Growth;Health;High Fat Diet;Human;Hydrolysis;In Vitro;Incidence;Individual;Intervention;Intestinal Absorption;Intestines;Lead;Lecithin;Link;Lipids;Lipoproteins;Low-Density Lipoproteins;Lymphatic System;Lysophospholipase;Lysophospholipids;Malignant Neoplasms;Mass Spectrum Analysis;Mediator of activation protein;Mentors;Metabolic;Metabolism;Metastatic Neoplasm to the Bone;Monitor;Mus;Neoplasm Metastasis;Nonesterified Fatty Acids;Obesity;Outcome;Overweight;Pathway interactions;Patients;Phospholipase A2;Phospholipase D;Phospholipids;Plants;Plasma;Postmenopause;Pre-Clinical Model;Prevalence;Process;Production;Reaction;Request for Proposals;Research;Research Personnel;Research Training;Risk Assessment;Risk Factors;Signal Transduction;Stomach;Testing;Tracer;Training;Underrepresented Minority;United States;United States National Institutes of Health;Weight;Woman;Work;anticancer research;base;cancer risk;cancer subtypes;career development;diet and cancer;dietary constituent;dietary manipulation;disorder risk;experience;feeding;food consumption;inhibitor/antagonist;lysophosphatidic acid;malignant breast neoplasm;metabolomics;migration;minority scientist;mouse model;nutrition;obesity risk;particle;response;sedentary lifestyle;skills;stable isotope;translational study;tumor growth;uptake


application_id: 9099545
project_number: 5F31NS092418-02
project_title: Determination of the epigenetic regulation of gene transcription by MeCP2 in neurons
administering_ic: NINDS
award_notice_date: 2016-06-23
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: NS
serial_number: 092418
program_official: MAMOUNAS, LAURA
project_start_date: 2015-07-01
project_end_date: 2017-05-05
study_section: Special Emphasis Panel[ZRG1-F03B-D(20)L]
contact_pi_person_id: 12337891
contact_pi: RIEDMANN, CAITLYN M
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): Over 90% of the cases of the devastating neurodevelopmental disorder Rett Syndrome (RTT) which affects 1 in 10000 girls is due to loss of function mutations in the X-linked methyl CpG binding protein 2 (MeCP2). MeCP2 is expressed in low levels throughout the body and during neurogenesis but is expressed at a level equivalent to linker histone H1 in mature neurons reaching a stoichiometry of one molecule MeCP2 per two nucleosomes the basic repeating unit of chromatin. Many RTT symptoms have been traced to MeCP2 mutations in neurons within specific regions of the brain and glial cells. Therefore determining the principles of MeCP2 mediated regulation is critical for understanding RTT pathology.  MeCP2 and H1 compete to bind nucleosomes at their DNA entry/exit dyad and lead to distinct chromatin structures with specific transcriptional outcomes. The first aim of this study will be to determine what nucleosomes throughout the genome are regulated by MeCP2. The genome-wide transcriptional deregulation observed in cells with mutated MeCP2 indicate that MeCP2 binds to specific nucleosomes throughout neurogenesis and during differentiation to drive proper expression patterns. Furthermore glial cell transcriptional deregulation due to MeCP2 mutations also contribute to RTT phenotypes indicating that MeCP2's regulation is cell type specific. Nucleosome chromatin immunoprecipitation coupled with high throughput sequencing (nuc-ChIP-seq) will be used to generate MeCP2-bound nucleosome maps for neurons during neurogenesis mature neurons and for glial cells. In addition to determining the target nucleosomes/genes of MeCP2 regulation these maps will also identify what histone tail post translational modification (PTMs) patterns associate with/signal for MeCP2 binding.  By binding to the DNA entry/exit dyad of nucleosome MeCP2 and H1 alter 'nucleosome breathing' the spontaneous dissociation of the DNA from the histone octamer thereby regulating the accessibility of DNA target sites usually buried within chromatin to their binding proteins. Therefore the second aim will be to determine how MeCP2 influences nucleosome stability and dynamics. Frster resonance energy transfer (FRET) will be performed on mononucleosomes and restriction enzyme digest analysis on in vitro multi- nucleosome arrays to determine the intrinsic binding activity of MeCP2 to both the individual nucleosome and to chromatin. These in vitro arrays will be modified to determine how specific epigenetic factors such as DNA methylation and specific histone tail PTM patterns regulate this binding. Furthermore RTT-causing MeCP2 mutations will be utilized in order to determine how these binding properties are altered in disease states.  By combining next generation sequencing (aim 1) with detailed binding assays (aim 2) this study will generate a highly detailed and global view of MeCP2 mediated transcriptional regulation in cells important in brain development thereby providing important insights into RTT pathology and therapeutic targets.

project_terms:
Affect;Atomic Force Microscopy;Base Pairing;Binding;Binding Proteins;Biochemical;Bioinformatics;Biological Assay;Brain;Breathing;Cells;Chromatin;Chromatin Structure;Conflict (Psychology);Coupled;DNA;DNA Methylation;DNA-Binding Proteins;Development;Disease;Dissociation;Energy Transfer;Environment;Epigenetic Process;Female;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Genetic;Genetic Transcription;Genome;Genomic DNA;Growth;Hand;High-Throughput Nucleotide Sequencing;Higher Order Chromatin Structure;Histocompatibility Testing;Histone H1;Histone H1(s);Histones;Homeostasis;In Vitro;Individual;Lead;Link;Location;Maintenance;Maps;Mediating;Methyl-CpG-Binding Protein 2;Molecular;Movement;Mutate;Mutation;Nature;Neurodevelopmental Disorder;Neuroglia;Neuronal Differentiation;Neurons;Nucleosomes;Outcome;Pathology;Pattern;Phenotype;Positioning Attribute;Post-Translational Protein Processing;Process;Property;Proteins;Recruitment Activity;Regulation;Reporting;Resolution;Rett Syndrome;Signal Transduction;Site;Speech;Structure;Symptoms;Tail;Tandem Repeat Sequences;Techniques;Testing;Time;Transcriptional Regulation;Work;analytical ultracentrifugation;biophysical techniques;brain cell;cell type;chromatin immunoprecipitation;developmental disease/disorder;epigenetic marker;epigenetic regulation;genome-wide;girls;insight;loss of function mutation;neurogenesis;next generation sequencing;prevent;public health relevance;relating to nervous system;restriction enzyme;stoichiometry;targeted treatment;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Most cases of the devastating neural developmental disorder Rett Syndrome characterized by apparently normal development for the first 6-18 months followed by developmental regression and stagnation complete loss of speech and hand stereotypies replacing purposeful hand movements are due to mutations in the neural protein MeCP2 (methyl CpG binding protein 2). This project will determine how MeCP2 interprets its genetic environment to properly regulate gene transcription in neurons and how this interpretation is changed in Rett Syndrome so that targeted therapies and treatments can be established.


application_id: 9099429
project_number: 1R15DE025960-01
project_title: Essential role of Rdh10 and Retinoic Acid in salivary gland organogenesis
administering_ic: NIDCR
award_notice_date: 2016-03-18
opportunity_number: PA-13-313
application_type: 1
activity_code: R15
ic: DE
serial_number: 025960
program_official: CHANDER, PREETHI
project_start_date: 2016-04-01
project_end_date: 2019-11-30
study_section: Special Emphasis Panel[ZRG1 MOSS-U (82)]
contact_pi_person_id: 11258094
contact_pi: SANDELL, LISA L
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): Many people suffer from loss of salivary gland function. Thus knowledge of salivary gland biology is an important research goal. Elucidating the developmental mechanisms that regulate organogenesis of a salivary gland within an embryo is a necessary first step toward developing therapies to replace or regenerate damaged glands. Key issues that can be addressed by examining embryonic salivary gland development include identifying the biological signals that stimulate growth and branching of the saliva-producing gland epithelium or that stimulate growth of essential gland nerves. Utilizing our expertise in developmental biology and mouse genetic tools for the study of Vitamin A metabolism we have recently identified that enzymatic metabolism of Vitamin A to produce the powerful hormone-like molecule Retinoic Acid is an essential biological mechanism regulating embryonic development of submandibular salivary glands. We have shown that Retinoic Acid regulates growth and branching of salivary gland epithelium in vivo and in vitro. For the current study we propose to investigate what cellular processes of epithelium branching growth are regulated by Retinoic Acid. We will examine embryonic salivary gland development in mice with a mutation in Rdh10 which are deficient in production of Retinoid Acid because they lack the major enzyme responsible for metabolism of Vitamin A. We will determine whether the defects in growth and branching of salivary gland epithelium result from abnormal cell proliferation basement membrane remodeling or formation of stable clefts between branches. We will complement our analysis of mouse embryonic glands by examining salivary glands grown in culture. These experiments will allow us to determine which cellular mechanisms of epithelium growth and branching are regulated by Retinoic Acid signaling. For the current investigation we propose also to examine the role of Retinoic Acid in regulating development of essential salivary gland nerves. We will determine if Retinoic Acid signaling regulates neuron number or neurite outgrowth and will determine if Retinoic Acid impacts nerve development via direct action in non-epithelial gland tissues or if Retinoic Acid impacts nerve formation indirectly via influence
on the epithelium. Knowledge gained from this study will serve as the groundwork for understanding how retinoid molecules impact salivary gland tissue morphogenesis.

project_terms:
Abnormal Cell;Acids;Address;Adult;All-Trans-Retinol;Basement membrane;Biological;Biology;Biomedical Engineering;Blood Vessels;Cell Count;Cell Proliferation;Cell physiology;Cleaved cell;Collagen Type IV;Complement;Computer software;Confocal Microscopy;Data;Defect;Deglutition;Dental Students;Dental caries;Development;Developmental Biology;Dose;Embryo;Embryonic Development;Enzymes;Epithelial;Epithelium;Fibronectins;Foundations;Future;Ganglia;Genes;Genetic;Gland;Goals;Growth;Health;Histone H3;Hormones;Human;Image Analysis;Immunology;In Vitro;Inflammation;Investigation;Knowledge;Length;Location;Maintenance;Mediating;Medical;Mesenchyme;Metabolic;Metabolism;Molecular;Molecular Genetics;Morphogenesis;Mus;Mutant Strains Mice;Mutation;National Institute of Dental and Craniofacial Research;Natural regeneration;Nerve;Nerve Tissue;Neurites;Neurons;Organ;Organogenesis;Peripheral;Personal Satisfaction;Production;Proteins;Regulation;Research;Research Priority;Retinal;Retinoids;Retinol dehydrogenase;Risk;Role;Saliva;Salivary;Salivary Gland Tissue;Salivary Glands;School Dentistry;Signal Transduction;Speech;Structure;Structure of parasympathetic ganglion;Testing;Tissues;Tretinoin;Universities;Veins;Vitamin A;Xerostomia;gland development;graduate student;in vivo;inhibitor/antagonist;insight;microscopic imaging;mutant;neuron development;novel;oral infection;oral tissue;programs;public health relevance;research study;therapy design;therapy development;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Knowledge of embryonic organ formation is a necessary first step toward developing therapies to restore or replace damaged salivary glands. We have recently identified that the powerful hormone-like molecule Retinoic Acid is an essential biological regulator of embryonic salivary gland development. For the current study we propose to investigate how Retinoic Acid controls formation of the saliva-producing epithelium and essential nerve tissue in developing submandibular salivary glands in mice.


application_id: 9098991
project_number: 9R15DA041708-02A1
project_title: Long-term effects early-life antipsychotic drug treatment
administering_ic: NIDA
award_notice_date: 2016-02-29
opportunity_number: PA-13-313
application_type: 9
activity_code: R15
ic: DA
serial_number: 041708
suffix: A1
program_official: WETHERINGTON, CORA LEE
project_start_date: 2016-03-01
project_end_date: 2020-02-29
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This is a renewal application for an R15 AREA grant to continue the research funded by our previous award ("Long-term effects of early-life antipsychotic drug treatment"). These grants are intended to stimulate research at educational institutions like Northern Kentucky University that support baccalaureate training but are not recipients of major NIH support. Over the past 20 years the use of antipsychotic drugs (APDs) in pediatric populations has increased eight-fold - a phenomenon that has garnered considerable attention in the scientific community and national media. This trend continues despite the relative absence of basic research documenting the effects of early-life APD exposure on later brain and behavioral function. One concern is that APD exposure during early brain development alters later sensitivity to drugs of abuse. Over the last three years our funded studies have shown that adult rats administered risperidone early in life are hyperactive and impulsive and demonstrate an enhanced locomotor response to D-amphetamine (AMPH) and a decreased density of forebrain dopamine transporters a primary target of psychostimulant drugs. Together these data suggest that early-life risperidone administration permanently alters the sensitivity of forebrain dopamine systems in ways that could magnify the behavioral effects of psychostimulant drugs. To continue investigating this hypothesis we propose to answer the following questions: 1) Does early-life APD administration alter the rewarding and cognitive-impairing effects of AMPH during adulthood? Conditioned place preference and an operant spatial working memory task will be used to determine if adult rats administered risperidone early in life are more sensitive to the rewarding and cognitive-impairing effects of AMPH respectively. 2) Does early-life APD administration alter the effects of AMPH on striatal dopamine and glutamate release during adulthood? AMPH elevates dopamine and glutamate release in the striatum - actions that are associated with AMPH's locomotor effects. The effects of AMPH on striatal dopamine and glutamate release will be characterized in adult rats administered risperidone early in life. 3) Does early-life APD administration alter markers of
forebrain synaptic function during adulthood? Since dopamine and norepinephrine transporters are the primary targets of AMPH the density of each transporter will be quantified in various forebrain regions of adult rats administered risperidone early in life. We will also compare the densities of dopamine and serotonin receptors as well as indices of dendritic architecture revealed via Golgi staining between adult rats as a function of early-life risperidone administration. Continued AREA funding will enable us to immerse undergraduates in enriching interdisciplinary research experiences in psychopharmacology developmental neuroscience and neurochemistry. Moreover it will ensure that researchers policy-makers and practitioners are provided with critically sought-after data regarding the long-term impact of prolonged APD treatment during childhood.

project_terms:
Acute;Address;Adult;Age;Amphetamines;Antipsychotic Agents;Architecture;Attention;Attention deficit hyperactivity disorder;Autoradiography;Award;Basic Science;Behavior;Behavioral;Brain;Canada;Child;Childhood;Cognitive;Collaborations;Communities;Corpus striatum structure;Data;Development;Disease;Disruptive Behavior Disorder;Dopamine;Dopamine Agonists;Dopamine Receptor;Dorsal;Dose;Drug Exposure;Drug Prescriptions;Drug abuse;Drug usage;Ensure;Europe;Exhibits;Funding;Glutamates;Golgi Apparatus;Grant;Impairment;Individual;Institution;Interdisciplinary Study;Investigation;Kentucky;Laboratory Rat;Life;Long-Term Effects;Measures;Mental disorders;Modification;Morphology;Neurosciences;Neurotransmitter Receptor;Office Visits;Pharmaceutical Preparations;Pharmacotherapy;Policy Maker;Population;Principal Investigator;Prosencephalon;Psychopharmacology;Rattus;Research;Research Personnel;Rewards;Risk;Risperidone;Short-Term Memory;Speed;Staining method;Stains;Substance abuse problem;Testing;Training;United States;United States National Institutes of Health;Universities;Work;base;boys;college;critical period;density;dopamine system;dopamine transporter;drug of abuse;experience;girls;indexing;laboratory experience;neurochemistry;noradrenaline transporter;postnatal;preference;programs;psychostimulant;public health relevance;relating to nervous system;response;serotonin receptor;sex;synaptic function;trend;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The use of antipsychotic drugs in pediatric populations has increased dramatically over the past 20 years despite a lack of basic research documenting the effects of developmental drug exposure on later brain and behavioral function. This research will use laboratory rats to ascertain whether early-life antipsychotic drug administration leads to greater behavioral and neural sensitivity to drugs of abuse in adulthood. This research will provide researchers policy-makers and practitioners with critical information regarding the impact of prolonged antipsychotic drug treatment during development on later risk of drug abuse and enhance laboratory experiences in neuroscience among college undergraduates in Kentucky.


application_id: 9098724
project_number: 5R01GM079684-08
project_title: The Regulation of Smoothened in Hedgehog Signaling
administering_ic: NIGMS
award_notice_date: 2016-06-09
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: GM
serial_number: 079684
program_official: MELILLO, AMANDA A
project_start_date: 2008-07-01
project_end_date: 2018-06-30
study_section: Development - 1 Study Section[DEV1]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
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): Hedgehog (Hh) proteins function as morphogens and play critical roles in pattern formation and cell growth control. Dysregulation and dysfunction of the Hh signaling pathway induces diverse types of cancers. The seven-pass transmembrane protein Smoothened (Smo) is required in both insects and mammals for transduction of the Hh signal. Our strategy is to use Drosophila as a simple and genetically tractable model system to explore the mechanisms of Hh signal transduction by the receptor complex. The long-term goal of our research is to elucidate how Hh signals are sensed and transmitted to control downstream biological events that ultimately govern cell growth and patterning. Although many components in the Hh pathway have been identified how the Hh signal is transduced through Patched (Ptc) to Smo is still unclear. We have discovered that Smo activation requires phosphorylation by multiple kinases including protein kinase A (PKA) casein kinase 1 (CK1) casein kinase 2 (CK2) and G protein-coupled receptor kinase 2 (Gprk2) and that phosphorylation leads to increased Smo cell surface levels and signaling activity. We show that Smo transduces Hh signals by directly recruiting a downstream Fused-Costal2 (Fu-Cos2) complex and that Fus- Cos2 protein complex promotes hyperphosphorylation of Smo uncovering a feedback mechanism essential for optimal Hh pathway activation. Furthermore we have identified protein phosphatase PP4 as a negative regulator of Smo. Results from our studies have suggested that the cell surface accumulation and intracellular trafficking of Smo play critical roles in regulating Hh-induced Smo activation. However many questions persist regarding the mechanism controlling Smo localization and trafficking. To begin address these questions we have recently discovered that the deubiquitinase USP8 promotes Smo signaling activity by preventing Smo ubiquitination and regulating Smo subcellular localization. Combined with the preliminary studies in the project our findings provide new tools and hypotheses for investigating the mechanisms of Smo signaling. In this project our central hypothesis is that Smo activation downstream of Hh is tightly controlled by its subcellular localization in which a novel kinase and small molecules promotes Hh signaling by enhancing the cell surface accumulation of Smo whereas ubiquitin inactivates Smo by promoting Smo endocytosis and degradation. We will use a combination of genetic and biochemical approaches in three Specific Aims: 1) To determine how a newly identified kinase regulates Smo phosphorylation and basolateral membrane localization; 2) to investigate the molecular mechanisms by which small molecules activate Smo in response to Hh stimulation; 3) to determine how Hh regulates the ubiquitin-mediated endosomal sorting of Smo via a novel E3 ligase of Smo.

project_terms:
Address;Basal cell carcinoma;Binding;Biochemical;Biological;Biological Models;Cancer Etiology;Cell surface;Cells;Complex;Congenital Abnormality;Cyclic AMP-Dependent Protein Kinases;Development;Diagnostic;Dimerization;Drosophila genus;Embryonic Development;Endocytosis;Erinaceidae;Event;Family member;Feedback;Functional disorder;G protein coupled receptor kinase;G-Protein-Coupled Receptors;Genetic;Goals;Health;High Pressure Liquid Chromatography;Homologous Gene;Insecta;Integral Membrane Protein;Investigation;Malignant Neoplasms;Mammals;Mass Spectrum Analysis;Mediating;Molecular;Pathway interactions;Pattern;Pattern Formation;Phospholipids;Phosphorylation;Phosphotransferases;Physiological;Play;Preventive;Process;Protein Tyrosine Kinase;Protein phosphatase;Proteins;Publishing;RNA interference screen;Recruitment Activity;Regulation;Research;Role;Signal Transduction;Signaling Molecule;Sorting - Cell Movement;Technology;Tertiary Protein Structure;Testing;Therapeutic;USP8 gene;Ubiquitin;Ubiquitination;Wing;base;basolateral membrane;cancer type;casein kinase I;casein kinase II;cell growth;design;fly;hedgehog signal transduction;insight;medulloblastoma;morphogens;novel;phosphatidylinositol 4-phosphate;prevent;protein complex;protein function;receptor;response;small molecule;smoothened signaling pathway;tool;trafficking;ubiquitin-protein ligase

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Hedgehog (Hh) signaling is known for its role in directing processes such as cell growth proliferation and differentiation during embryogenesis. Abnormal activation of Smo an atypical GPCR in the receptor complex results cancers such as basal cell carcinoma (BCC) and medulloblastoma. Investigation of the Smo signaling mechanisms the goal of this project will provide both insights into fundamental developmental problems and new strategies to design preventive and curative tools and treatments for cancers caused by deregulated Hh signaling.


application_id: 9098664
project_number: 4U01DA036158-04
project_title: Kentucky TRIALS Research Center
administering_ic: NIDA
award_notice_date: 2016-06-08
opportunity_number: RFA-DA-13-009
application_type: 4
activity_code: U01
ic: DA
serial_number: 036158
program_official: JONES, DIONNE
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: ZDA1-EXL-T(11)S
contact_pi_person_id: 1873108
contact_pi: LEUKEFELD, CARL G
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:
This cooperative agreement Center application the Kentucky TRIALS Substance Abuse and HIV Research Center (KY-TRIALS) is submitted by the University of Kentucky in cooperation with the Kentucky Department of Juvenile Justice community substance abuse service organizations and HIV service providers to respond to RFA-DA-13-009 "Translational Research on Interventions for Adolescents in the Legal System: TRIALS". This project focuses on filling the need for implementation studies to enhance continuity of care for juvenile justice Involved adolescents. Kentucky provides an ideal setting to study the implementation of evidence-based practices because of our longstanding Juvenile Justice and university relationship. KY-TRIALS is well-positioned to conduct rigorous research on implementing evidence-based practices. The Overall Aim of the KY-TRIALS Substance Abuse and HIV Research Center is to collaborate in developing and testing implementation strategies and associated measures to improve the continuum of substance abuse and HIV prevention and treatment services for youth under juvenile justice supervision. The KY-TRIALS approach Incorporates theoretical frameworks of implementation science (Proctor et. al. 2009; Aarons et al. 2011) and organizational change to examine how evidence-based practices are implemented into practice in organizational settings. Our conceptual approach draws upon our experience in implementation science and previous cooperative studies to carry out the KY-TRIALS research center vision and research. This application presents 4 proven and partner-rich Center Committees: 1) Design and Measures 2) Study Implementation 3) Data Management and Analysis and 4) Publications for achieving success in the aims of TRIALS in concert with our KY-TRIALS Center Steering Committee the national TRIALS Steering Committee and the National Institute on Drug Abuse. Letters of commitment include our state's Juvenile Justice Commissioner; Acting Director of the Division of Behavioral Health; Executive Director of the Kentucky Office of Drug Control Policy; juvenile justice officials; and community substance abuse and HIV service providers to support our innovative vision.

project_terms:
AIDS prevention;Address;Adolescence;Adolescent;Adoption;Area;Clinical Research;Communities;Community Services;Continuity of Patient Care;Criminal Justice;Data;Data Analyses;Disease;Drug Controls;Drug abuse;Environmental Risk Factor;Evidence based intervention;Evidence based practice;Federal Hospitals;HIV;Intervention;Justice;Kentucky;Knowledge;Legal system;Letters;Measures;National Institute of Drug Abuse;Organizational Change;Outcome;Pharmaceutical Preparations;Policies;Positioning Attribute;Provider;Publications;Research;Research Personnel;Research Project Grants;Services;Site;Staging;Substance abuse problem;Supervision;Testing;Translational Research;U-Series Cooperative Agreements;United States Public Health Service;Universities;Vision;Vision research;Youth;adolescent substance abuse;alcohol research;base;behavioral health;cooperative study;data management;design;experience;implementation research;implementation science;improved;innovation;juvenile justice system;prevention service;response;success;theories

public_health_relevance:
The Overall Aim of the KY-TRIALS Substance Abuse and HIV Research Center is to collaborate in developing and testing implementation strategies and associated measures to Improve the continuum of substance abuse and HIV prevention and treatment services delivered to youth under juvenile justice supervision. The KY-TRIALS Center has the potential to make a significant contribution to an understudied area by providing knowledge on adolescent assessment for substance abuse disorders and HIV community implementation science and theory juvenile justice and evidence-based practices. Successful completion of the KY-TRIALS cooperative agreement will provide essential information to add significant new and groundbreaking knowledge about implementation science and to improve the continuity of care for adolescents involved in juvenile justice.


application_id: 9098561
project_number: 5R01AA023681-03
project_title: Mechanisms for alcohol induced gut barrier dysfunction in ALD
administering_ic: NIAAA
award_notice_date: 2016-06-22
application_type: 5
activity_code: R01
ic: AA
serial_number: 023681
program_official: GAO, PETER
project_start_date: 2014-07-05
project_end_date: 2019-06-30
study_section: ZAA1-GG(50)P
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
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: 2016-07-01
project_abstract:
It is increasingly recognized that gut flora and gut barrier function play a pivotal role in thepathogenesis of several forms of liver disease including ALD. Gut-derived endotoxins normally penetrate thegut epithelium in only trace amounts due to tightly regulated intestinal barrier function. However endotoxinleakiness is increased under pathological conditions including alcohol abuse. The barrier function ofintestinal epithelium Is provided in part by paracellular apical junction complexes including tight andadherens junctions and by a mucus layer. In our initial systems biology approach to ALD we found that intestinal trefoil factor (ITF) was by far themost altered (~50-fold down regulated) protein in the liver following chronic alcohol feeding in rats andsubsequent studies also showed marked down regulation of ITF mRNA and protein in the intestines ofalcohol fed mice. ITF plays a critical role in the formation and stabilization of intestinal mucus barrier andenhancement of rapid intestinal repair "restitution". Formation and restitution ofthe barrier is also dependenton uninterrupted mucosal blood flow. Intestinal epithelial cells are positioned between an anaerobic lumenand a highly metabolic lamina propria forming a steep physiologic oxygen gradient. Increased hypoxia-inducible factor (HIF) signaling represents a major adaptive response to hypoxic stress by upregulating avariety of gene products such as ITF and mucins to form an integrated epithelial barrier. Our preliminarystudies demonstrated that chronic alcohol administration decreases intestinal HIF-2a ITF and tight junctionprotein expression resulting in increased endotoxemia and ultimately liver injury. Moreover supplementationwith a probiotic strain Lactobacillus rhamnosus GG (LGG) increased intestinal HIF-2a and ITF expressiondecreased endotoxemia and attenuated alcohol induced liver injury. We hypothesize that alcohol exposurecauses detrimental metabolic changes favoring intestinal oxidative stress inflammation and alterations ofHIF responsive signaling with decreased ITF leading to intestinal barrier dysfunction blood endotoxemiaand ALD. We postulate that probiotic supplementation will attenuate alcohol-induced intestine and liverinjury in part by increasing HIF-mediated expression of mucus protective factors such as ITF in the intestine.We test our hypothesis with 4 specific aims using in vitro animal and human studies approaches. Ourultimate goal is the development of new therapies for ALD.RELEVANCE (See instructions):Alcohol overuse/abuse induces organ injury in multiple organs. This translational research project willexamine the mechanisms of the beneficial effects of probiotics on the intestine and the liver in anexperimental mouse model of alcoholic liver disease (ALD) and in mild human alcoholic hepatitis (AH).

project_terms:
Adherens Junction;Alcohol abuse;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Animals;Apical;Attenuated;Bacteria;Blood;Blood flow;Cells;Chronic;Complex;Defect;Development;Down-Regulation;Endotoxemia;Endotoxins;Epithelial;Epithelial Cells;Functional disorder;Goals;Human;Hypoxia;Hypoxia Inducible Factor;Immune response;In Vitro;Inflammation;Injury;Instruction;Intestines;Knockout Mice;Lactobacillus casei rhamnosus;Lamina Propria;Liver;Liver diseases;Mediating;Messenger RNA;Metabolic;Metabolic Pathway;Mucins;Mucous body substance;Mus;Organ;Oxidative Stress;Oxygen;Pathogenesis;Patients;Physiological;Play;Positioning Attribute;Principal Investigator;Probiotics;Process;Procollagen-Proline Dioxygenase;Proteins;Rattus;Recombinants;Research Project Grants;Role;Sampling;Signal Transduction;Stress;Supplementation;Systems Biology;Testing;Tight Junctions;Translational Research;alcohol effect;alcohol exposure;alcohol response;comparative efficacy;feeding;gain of function;gastrointestinal epithelium;gene product;intestinal epithelium;liver injury;loss of function;mouse model;novel therapeutics;probiotic supplementation;probiotic therapy;protective effect;protein degradation;protein expression;repaired;response;treatment effect;trefoil factor


application_id: 9098197
project_number: 1R15HD087911-01
administering_ic: NICHD
award_notice_date: 2016-07-08
opportunity_number: PA-13-313
application_type: 1
activity_code: R15
ic: HD
serial_number: 087911
program_official: TAYMANS, SUSAN
project_start_date: 2016-07-08
project_end_date: 2019-06-30
study_section: Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section[IRAP]
contact_pi_person_id: 10319238
contact_pi: TAYLOR, KIRA C.
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
budget_start_date: 2016-07-08
project_title:
The interaction between NAT2 acetylator status and exposure to tobacco smoke on ovarian reserve and in vitro fertilization outcomes.

project_abstract:
DESCRIPTION (provided by applicant): The prevalence of impaired fecundity (>11%) and infertility (>6%) among women in the United States is considerable and a significant proportion (>15%) of infertility remains unexplained by current scientific knowledge. The aim of this research is to further the understanding of the role that gene-environment interactions play in infertility. The deleterious effects of smoking on ovarian reserve and on in vitro fertilization procedures are evident but more research needs to be done to understand the cumulative effects of lifetime exposure to smoking and to secondhand smoke on infertility. Exposure to tobacco smoke may be more harmful in patients who carry a particular slow-acetylator form of NAT2 a gene which plays an important role in metabolism of aromatic amines present in tobacco smoke. In this study the effects of smoking alone NAT2 alone and their combined effects on ovarian reserve and in vitro fertilization (IVF) will be estimated. Past and current exposure to tobacco smoke will be determined by questionnaires and by assaying cotinine a biomarker of smoking that will be measured in urine and follicular fluid. In Aim 1 the cumulative effect of lifelong exposure to active and passive smoking (secondhand smoke) on ovarian reserve and IVF success will be estimated. Ovarian reserve will be determined by measuring anti-Mllerian hormone levels and antral follicle count. Success of IVF will be determined by oocyte retrieval count fertilization rate and establishment of a clinical pregnancy. In Aim 2 patients will be tested to determine whether they carry the slow-acetylator form of the NAT2 gene and it will be determined whether these individuals experience increased ovarian reserve or lower IVF success. Because NAT2 detoxifies aromatic and heterocyclic amines and is responsible for variability in the effect of arylamine and arylhydrazine drugs throughout the lifespan the slow NAT2 phenotype may be associated with measures of ovarian reserve and IVF outcomes regardless of exposure to tobacco smoke. In Aim 3 the interaction between smoking and NAT2 on ovarian reserve and IVF success will be investigated. It is hypothesized that the effects of tobacco smoke exposure on these outcomes will be exacerbated among slow acetylators. Findings from this work will contribute to the understanding of infertility especiall how environmental/behavioral risk factors and genetic susceptibility may interact to reduce a woman's fertility and shorten her reproductive lifespan.

project_terms:
Adolescence;Antral;Aromatic Amines;Behavioral;Biological Assay;Biological Markers;Breathing;Carcinogens;Childhood;Clinical;Consumption;Cotinine;Dose;Drug toxicity;Environmental Tobacco Smoke;Exposure to;Female infertility;Fertility;Fertilization;Fertilization in Vitro;Follicular Fluid;Genes;Genetic Predisposition to Disease;Haplotypes;Individual;Infertility;Knowledge;Longevity;Malignant Neoplasms;Manuscripts;Measures;Metabolism;Modeling;NAT2 gene;Oocytes;Outcome;Ovarian;Passive Smoking;Patient Recruitments;Patients;Pharmaceutical Preparations;Phenotype;Play;Population;Pregnancy;Prevalence;Procedures;Questionnaires;Research;Retrieval;Risk Factors;Role;Smoking;Subfecundity;Testing;Time;Tobacco;Tobacco smoke;Toxic effect;United States;Urine;Woman;Work;Xenobiotics;base;environmental tobacco smoke exposure;experience;gene environment interaction;heterocyclic aromatic amines;mullerian-inhibiting hormone;public health relevance;reproductive;response;success;tobacco exposure;urinary

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The aim of this research is to further the understanding of the role that gene-environment interactions play in female infertility. The harmful effects of smoking on fertility may be even more pronounced in patients who carry a particular slow-acetylator form of a gene NAT2 which plays an important role in the metabolism of aromatic amines found in tobacco smoke. The effects of active and passive smoking NAT2 and their combined effects on ovarian reserve and in vitro fertilization will be estimated.


application_id: 9096749
project_number: 5R01DK080770-06
project_title: Renal Osteodystrophy: A Fresh Approach
administering_ic: NIDDK
award_notice_date: 2016-06-28
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 080770
program_official: CHAN, KEVIN E
project_start_date: 2009-03-01
project_end_date: 2020-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 7875292
contact_pi: MALLUCHE, HARTMUT H
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Age;Alendronate;Alkaline Phosphatase;Aorta;Biochemical;Blood;Blood Tests;Bone Density;Bone Diseases;Bone Pain;Bone Resorption;Categories;Chronic;Chronic Kidney Failure;Clinical;Control Groups;Coronary;Data;Dialysis procedure;Disease;End stage renal failure;Endocrine System Diseases;Enrollment;Event;FDA approved;Forteo;Fracture;Funding;Gender;General Population;Goals;Health;Heart Arrest;Heart Valves;Hip Fractures;Histologic;Individual;Kidney Diseases;Link;Malignant Neoplasms;Measures;Metabolic Diseases;Minerals;Mission;Monitor;Morbidity - disease rate;Myocardial Infarction;N-terminal;Operative Surgical Procedures;Osteogenesis;Osteoporosis;PTH gene;Pathway interactions;Patients;Physicians;Postmenopausal Osteoporosis;Procollagen;Quality of life;Race;Randomized;Randomized Controlled Trials;Renal Osteodystrophy;Renal function;Research;Risk;Safety;Science;Serum;Severities;Staging;Telephone;Testing;Therapeutic;Time;Treatment Cost;Treatment Protocols;United States;United States National Institutes of Health;Vascular calcification;Visit;X-Ray Computed Tomography;arm;base;bone;bone loss;bone mass;bone turnover;calcification;cardiovascular risk factor;cinacalcet;clinical practice;coronary artery calcification;cost;detector;fibroblast growth factor 23;high risk;improved;individualized medicine;mortality;novel;response;socioeconomics;stroke;tartrate-resistant acid phosphatase;treatment group


application_id: 9096671
project_number: 5T03OH010637-03
project_title: The Environmental Health Science Program at Western Kentucky University
administering_ic: NIOSH
award_notice_date: 2016-05-27
opportunity_number: PAR-10-288
application_type: 5
activity_code: T03
ic: OH
serial_number: 010637
program_official: MAPLES, ELIZABETH
project_start_date: 2014-07-01
project_end_date: 2017-06-30
study_section: ZOH1-JFK(50)
contact_pi_person_id: 9781877
contact_pi: GOLLA, VIJAY
other_pis: Not Applicable
congressional_district: 02
department: PUBLIC HEALTH & PREV MEDICINE
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 PUBLIC HEALTH
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Western Kentucky University (WKU) is seeking NIOSH Training Program Grant (TPG) support for its baccalaureate degree curriculum in Environmental Health Science (EHS) to recruit and provide six students with training and professional opportunities as well as enhance the diversity of students in the program. The purpose of the EHS program is to nurture the broad base of applied skills required of professionals for a career in environmental occupational health and safety. It will also increase
the diversity of students attracted and retained in the program. The EHS program is built upon a comprehensive education in basic and applied sciences that provides students with the background and technical skills necessary for recognizing identifying assessing and controlling environmental and occupational health stressors and the interrelations between environmental factors and human health. In response to its Advisory Committee recommendations and in recognition of the national trend in the profession whereby practitioners are required to take on a more integrated practice of industrial hygiene environmental health management and occupational safety the EHS program has undergone a number of revisions since inception. Adequate academic preparation of our students is the result of a carefully planned curriculum that is supplemented with extracurricular activities and project-based or service learning experiences. The current EHS curriculum consists of 120 semester hours and offers up to 70 credit hours of industrial hygiene environmental science safety and related areas including electives. To that end the EHS faculty continues to actively create a unique and effective learning environment for students by integrating project- based or service learning into the academic program. Project-based learning essentially involves incorporating into the curriculum a steady progression of "hands on" experiences that allow for increasing student involvement and responsibility as they make the transition from observer to participant to practitioner. This trend is also consistent within the regional needs of industries
consultants other private companies and governmental or non-governmental organizations served by the WKU EHS program. For this region and beyond employers comprised of small to medium-sized companies employing 30- 500 employees and an individual is typically designated as the EHS Coordinator/Supervisor/Manager and is often assigned the responsibility of dealing with all day-to-day matters pertaining to industrial hygiene safety and environmental health management. The necessity of applying a broad base of technical skills and problem solving abilities within such a complicated regulatory framework makes the field of EHS Management one of the most complex and challenging endeavors. Our region is in great need of academic programs capable of producing qualified graduates to meet the challenges of this diverse and rapidly changing field. Curriculum implementation has provided significant contributions to WKU's offerings and will continue to be important in producing academically prepared students with the required baccalaureate degrees. WKU's experience with programs of a similar nature the successes of the graduates with this major and the unique combination of our course inventories faculty qualifications and student experiences makes the institution the appropriate place to implement the NIOSH TPG. A defined and growing need for graduates of the program suggests that the program will be successful far beyond the three year period requested for the current TPG support. Suffice it to note that support awarded through this application will enhance the continuation of this process of EHS curriculum implementation for the six students that would be selected. The opportunity to expand the core and adjunct faculty committed to the program and attract and support a diversity of qualified students especially minority students will greatly improve the probability of continued program success and significantly amplify the quality of students' experiences. Our EHS students continue to participate in project based learning and as well as present their results at the annual WKU REACH week and the Kentucky Public Health Association conference. In addition students that would be awarded the NIOSH TPG will be required to attend and present posters at the annual University of Cincinnati/NIOSH PRP symposium. Finally it is important to reiterate the fact that students who complete the requirements for the EHS degree program are fundamentally equipped with theoretical analytical and practical skills necessary to adequately anticipate recognize identify and control environmental occupational health and safety problems.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Western Kentucky University (WKU) is seeking NIOSH Training Program Grant (TPG) support for its Environmental Health Science (EHS) baccalaureate degree curriculum so as to improve the broad base of applied skills the quality and diversity of academically prepared students that would take up careers as industrial hygienists occupational safety scientists or environmental health managers which is inadequate in the current regional workforce. A strong environmental occupational health and safety training and qualifications would be essential to the successful performance of graduates of our program. WKU's experience with programs of similar nature the successes of our EHS graduates and the unique/interdisciplinary combination of course offerings faculty qualifications
and commitment to experiential learning and underserved students in its region makes WKU the appropriate place for the NIOSH TPG program.


application_id: 9096271
project_number: 4R01NR014189-05
project_title: Early Detection and Prevention of Mild Cognitive Impairment due to Cerebrovascular Disease
administering_ic: NINR
award_notice_date: 2016-06-14
opportunity_number: RFA-NR-12-010
application_type: 4
activity_code: R01
ic: NR
serial_number: 014189
program_official: TULLY, LOIS
project_start_date: 2012-09-26
project_end_date: 2018-06-30
study_section: ZNR1-REV-T(13)
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: MOSER, DEBRA KAY
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): There is a great unmet need to distinguish clinically between the different causes of cognitive impairment in elderly individuals for the sake of early diagnosis and therapeutic intervention designed to improve outcomes for patients. The University of Kentucky Alzheimer's Disease Center (UK-ADC) has been at the forefront of studying the most prevalent causes of Non-AD MCI demonstrating that over two-thirds of elderly patients have non-AD brain conditions that deleteriously affect cognition. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). This application focuses on defining the pathological underpinnings and relationships of specific risk factors to MCI-CVD developing clinical diagnostic criteria for MCI-CVD using imaging serum and CSF biomarkers that will also allow longitudinal evaluation and assessment of therapeutic interventions in MCI-CVD. As such the current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.

project_terms:
Affect;Age-Years;Alzheimer's Disease;Area;Autopsy;Biological;Biological Markers;Blood;Brain;Brain Diseases;Brain Pathology;Cardiovascular Diseases;Cerebrospinal Fluid;Cerebrovascular Disorders;Clinical;Clinical Trials;Cognition;Cognitive;Data;Dementia;Diagnostic;Diagnostic Imaging;Doctor of Philosophy;Early Diagnosis;Elderly;Ensure;Etiology;Evaluation;Health;Healthcare;Image;Impaired cognition;Individual;Intervention;Kentucky;Medical;Microvascular Dysfunction;Modification;Natural History;Neuropsychological Tests;Pathology;Patients;Persons;Placebo Control;Population;Prevalence;Prevention;Randomized;Recording of previous events;Research Personnel;Risk Factors;Scientific Advances and Accomplishments;Serum;Staging;Statistical Models;Testing;Therapeutic Intervention;Universities;bench to bedside;cohort;design;digital;disorder risk;improved outcome;mild cognitive impairment;multidisciplinary;older patient;programs;standard of care;success;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Mild cognitive impairment (MCI) is often conflated with early Alzheimer's disease (AD) although a large proportion of individuals with MCI lack AD pathology. Especially among individuals beyond 85 years of age the prevalence of non-AD brain diseases such as cerebrovascular disease (CVD) surpasses that of advanced AD. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). The current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.


application_id: 9096152
project_number: 4P30GM106396-04
project_title: PILOT PROJECT PROGRAM
administering_ic: NIGMS
award_notice_date: 2016-07-28
opportunity_number: PAR-10-196
application_type: 4
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8531
contact_pi_person_id: 1882793
contact_pi: EATON, JOHN W
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The overall goal of the Phase III MT COBRE is to ensure that the novel targets and compounds that have been identified by MT COBRE faculty are translated to pivotal human clinical trials. To that end the Pilot Grant Program will have as its major objective the identification and initial funding of research projects to develop novel pre-clinical therapeutic agents identified by MT COBRE Program investigators. Although the theme of this funding mechanism will be translational development of novel therapeutics and priority will be given to translational studies with a high potential for advancement to clinical studies other meritorious grants may be funded as well. It is the intent that these developmental projects will lead to R01 and other competitive grant funding through expansion or re-direction of prior COBRE projects. The Pilot Grant Program will have a total 5-year budget of $1725000; comprised of $575000 from the MT COBRE grant $500000 from the Executive Vice President for Research and $650000 from the James Graham Brown Cancer Center discretionary funds (see detailed description below). The applications will be solicited by an RFP process and will be reviewed by the MT COBRE Steering Committee.

project_terms:
Budgets;Cancer Center;Centers of Research Excellence;Clinical Research;Clinical Trials;Development;Ensure;Faculty;Funding;Funding Mechanisms;Goals;Grant;Human;Lead;Molecular Target;Phase;Process;Research;Research Personnel;Research Project Grants;Therapeutic Agents;Translating;novel;novel therapeutics;pre-clinical;programs;translational study


application_id: 9096151
project_number: 4P30GM106396-04
project_title: Animal Model Core
administering_ic: NIGMS
award_notice_date: 2016-07-28
opportunity_number: PAR-10-196
application_type: 4
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8530
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
PROJECT SUMMARY (See instructions): The goal of the University of Louisville Molecular Targets COBRE Core D is to facilitate the rapid translation of novel approaches to cancer prevention diagnosis and treatment through the use of transgenic mouse models of cancer. In particular. Core D will facilitate the translational objectives of University of Louisville COBRE-related investigators by developing coordinated resources techniques expertise and several colonies of transgenic mice for the safety and efficacy testing of novel anti-cancer approaches. The initial goal will be to establish colonies of the transgenic mice and to develop methods for longitudinal monitoring of tumor progression or regression without the need to euthanize the animals. Once the core is established the long-term objectives will be to provide access of transgenic mouse models of cancer to junior and senior cancer researchers at the University of Louisville including past and present COBRE investigators in order to facilitate the testing of novel anti-cancer compounds and strategies. The specific objectives are to: (i) Maintain distribute and provide pre-clinical toxicity and efficacy support for transgenic mouse models of melanoma childhood neuroblastoma lung breast prostate colon pancreatic and hematological cancers; (ii) Provide technical support for transgenic mouse genotyping specimen collection and processing and PK analyses of novel anti-cancer agents; and (iii) Conduct state-of-the-art diagnostic imaging services for the detection of tumors and response to novel therapeutic agents. In summary we propose a core facility that will procure and breed transgenic mouse models of several common cancer types and that will provide technical services to facilitate the testing of novel strategies and drugs developed at the University of Louisville.

project_terms:
Animal Model;Animals;Breast;Breeding;Centers of Research Excellence;Childhood Melanoma;Clinic;Colon;Core Facility;Detection;Diagnosis;Diagnostic Imaging;Genotype;Goals;Instruction;Laboratories;Lung;Malignant Neoplasms;Methods;Modality;Modeling;Molecular Target;Monitor;Neuroblastoma;Pancreas;Phase;Prostate;Research Personnel;Resources;Safety;Services;Site;Specimen Handling;Techniques;Testing;Therapeutic Agents;Time;Toxic effect;Transgenic Mice;Translations;Universities;Xenograft Model;cancer prevention;cancer type;cost;efficacy testing;efficacy trial;human disease;human subject;mouse model;novel;novel anticancer drug;novel strategies;novel therapeutics;phase I trial;pre-clinical;prevent;research study;response;safety testing;sample collection;success;tumor;tumor progression

public_health_relevance:
RELEVANCE (See instructions): Core E will support pre-clinical safety and efficacy trials of novel compounds and strategies to detect prevent and treat cancer so that our COBRE investigators can rapidly move these agents and strategies from laboratory benches into cages and then phase I trials of human subjects suffering with cancer.


application_id: 9096150
project_number: 4P30GM106396-04
project_title: Molecular Modelling Core
administering_ic: NIGMS
award_notice_date: 2016-07-28
opportunity_number: PAR-10-196
application_type: 4
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8529
contact_pi_person_id: 7821204
contact_pi: TRENT, JOHN O
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
PROJECT SUMMARY (See instructions):  One of the overriding goals of the Brown Cancer Center is translational research. One way to achieve this is to provide a conduit for investigators studying particular molecular targets to conduct structure-based drug design. The Molecular Modeling Core Facility is an integral part of the COBRE which is used by all the COBRE investigators and many NIH funded investigators. It provides a natural entryway for structural biological approaches developed by COBRE scientists and through its close interaction with the NMR Center biophysicists molecular biologists chemists medicinal chemists computer scientists and biochemists. The overall goal of the Facility is rationalization prediction and design i.e. the rationalization of experimental data the prediction of new empirical experiments and the structure-based drug design of new agents. The aims of the Core are to: 1. provide equipment and expertise for a variety of modeling applications 2. facilitate structure-based drug design for drug discovery and drug development including facilitating testing of targeted compounds. 3. provide a bridge between crystallography NMR medicinal chemistry and other disciplines 4. provide a collaborative environment for the BCC 5. inform the Structural Biology Program of advances in the field and to implement them 6. educate the Structural Biology Program and others on possible enhancements to their research 7. train students on "state of the art" molecular modeling These aims will be met by maintaining state-of-the-art software and computafional resources which will support collaborative interactions with COBRE and other investigators.

project_terms:
Biological;Cancer Center;Centers of Research Excellence;Chemicals;Code;Computational Biology;Computer Hardware;Computer Simulation;Computer software;Computers;Consult;Core Facility;Crystallography;Data;Data Analyses;Development;Discipline;Doctor of Philosophy;Drug Design;Equipment;Funding;Goals;Individual;Instruction;Maintenance;Mission;Modeling;Molecular;Molecular Models;Molecular Target;New Agents;Pharmaceutical Chemistry;Phase;Rationalization;Research;Research Personnel;Resource Allocation;Resources;Route;Scientist;Structure;System;Testing;Training;Translational Research;United States National Institutes of Health;Validation;base;collaborative environment;computing resources;design;drug development;drug discovery;experience;meetings;molecular modeling;novel;novel therapeutics;operation;programs;research study;screening;structural biology;student training;virtual

public_health_relevance:
RELEVANCE (See instructions): The Modeling Core is directly involved in drug discovery. It enables almost any investigator to determine if their system is targetable and provides potential compounds for testing as chemical probes or new drugs. This adds a new direct route for translational research that otherwise would not be available to many investigators.


application_id: 9096149
project_number: 4P30GM106396-04
project_title: NMR and Metabolomics Core
administering_ic: NIGMS
award_notice_date: 2016-07-28
opportunity_number: PAR-10-196
application_type: 4
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8528
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
PROJECT SUMMARY (See instructions): The primary aims of the NMR core are to provide infrastructure and support for structural analysis of target macromolecules their mutual interactions and with candidate drug molecules obtained from in silico searches and optimization and metabolomics of cancer cells and tissue. This includes stable isotope labeling strategies including N-15 and C-13 precursors. Our goals continue to be to streamline both data collection and analysis as well as introduce new labeling strategies to provide more detailed information about specific metabolic pathways via Stable Isotope Resolved Metabolomics (SIRM). This includes NMR structural and biophysical analysis of macromolecules and their interactions with small molecules as well as extensive use of the metabolomics capabilities of the Core as a part of the drug discovery/development process. A large fraction of research projects that use the facility are translational using purified components as well as animal models and human subjects. The NMR-based studies operate in tandem with activates of other Cores especially the Modeling Core and in the future with the Transgenic Mouse Core. NMR is one of the few techniques that provides localized imaging and high resolution high information content spectroscopy in vivo. This will be a major new direction of the Core.  The overall goals of the Core will be achieved via the following Specific Aims: 1. Provide NMR instrumentation and expertise for characterizing macromolecules and their interactions; 2. Provide the instrumentation and expertise for metabolomics studies; 3. Facilitate structure-based drug design for drug discovery and drug development; 4. Develop and implement new experiments and capabilities including stable isotope resolved metabolomics on small animals in vivo; 5. Educate members of the community on the specific capabilities of NMR for their research projects; 6. Provide training of students and fellows in cancer biochemistry and drug development. These Aims complement those of the other Cores in terms of the overall research mission of the Cancer Center and the University.

project_terms:
Animal Model;Animals;Automation;Binding;Biochemical;Biochemistry;Cancer Center;Chemistry;Collaborations;Communities;Complement;Computer Simulation;Consultations;Core Facility;DNA;Data Analyses;Data Collection;Development;Drug Design;Drug Targeting;Enzymatic Biochemistry;Experimental Designs;Future;Goals;Image;Instruction;Label;Malignant Neoplasms;Metabolic Pathway;Metabolism;Methods;Mission;Modeling;Molecular Models;Molecular Target;Nucleic Acids;Pathway Analysis;Pharmaceutical Preparations;Phase;Procedures;Process;Proteins;Research;Research Infrastructure;Research Project Grants;Resolution;Running;Sampling;Spectrum Analysis;Stable Isotope Labeling;Structure;Surface;Techniques;Technology;Tissues;Training;Transgenic Mice;Translational Research;Universities;Validation;base;biophysical analysis;cancer cell;data reduction;design;drug candidate;drug development;drug discovery;human subject;in vivo;instrumentation;macromolecule;member;metabolomics;molecular modeling;novel;research facility;research study;small molecule;stable isotope;student training

public_health_relevance:
RELEVANCE (See instructions): NMR provides high resolution information about drug targets and their interactions as well as metabolomics analyses at the atomic level that are critical to basic understanding of cellular metabolism and drug discovery and development.


application_id: 9096148
project_number: 4P30GM106396-04
project_title: Microarray Core
administering_ic: NIGMS
award_notice_date: 2016-07-28
opportunity_number: PAR-10-196
application_type: 4
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8527
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
PROJECT SUMMARY (See instructions): At the University of Louisville the instrument personnel and software resources for high-density microarray based gene expression and single nucleotide polymorphism (SNP) genotyping analyses are in place through an investment of the UofL James Graham Brown Cancer Center (JGBCC). Such global profiles can be obtained for tens of thousands of genes or SNP loci from cell populations or tissue material within one time saving and standardized experiment. Comparative analysis of global gene expression patterns on biological or pathologic material will provide crucial information on gene products and/or mutations which are involved in a cellular and/or disease process. The objective of the Microarray Core is to offer this highly advanced technology as well as sufficient opportunities for training and research applications for investigators. The Specific Aims of the Microarray Facility are to offer the following services to JGBCC investigators: 1. To provide high-quality services for microarray-based gene expression and genotyping analysis; 2. To continuously incorporate the newest array products and analysis tools into the menu of services provided; 3. To educate and train users in applications strengths and limitations of microarray technology; 4. To assist users in experimental design sample processing and data analysis; 5. To provide logistic support for project development grant applications and manuscript preparations applying microarray technology.  The Core presented here shall ensure that JGBCC investigators especially clinical faculty and research groups will be able to efficiently adopt this novel state-of-the-art technology for their research clinical and investigative goals using in vitro clinical specimen or animal model materials (using their approval protocols). It will be crucial for these investigators to have affordable access and expert support to the most advanced and sophisticated molecular technologies as part of the institutional resources provided to them.

project_terms:
Adopted;Animal Model;Applications Grants;Basic Science;Bioinformatics;Biological;Biometry;Cancer Center;Cells;Clinical;Clinical Research;Computer software;DNA;Data Analyses;Data Collection;Development;Disease;Educational workshop;Ensure;Experimental Designs;Gene Expression;Gene Expression Profile;Genes;Genetic Transcription;Genomic DNA;Genotype;Goals;Human;Human Resources;Hybridization Array;In Vitro;Individual;Instruction;Internet;Investments;Knowledge;Logistics;Malignant Neoplasms;Manuscripts;Microarray Analysis;Molecular;Molecular Target;Mus;Mutation;Nursing Faculty;Pathologic;Phase;Polymorphism Analysis;Population;Preparation;Procedures;Process;Protocols documentation;Provider;RNA;RNA amplification;Research;Research Personnel;Research Training;Resources;Sample Size;Sampling;Services;Single Nucleotide Polymorphism;Specimen;Technology;Time;Tissues;Training;Universities;base;comparative;density;gene product;instrument;novel;novel diagnostics;research study;tool;training opportunity;transcriptome

public_health_relevance:
RELEVANCE (See instructions): The Microarray Facility offers highly advanced microarray-based technologies for basic science and clinical research applications as well as opportunities for training to UofL investigators. This Facility has been and will be instrumental in advancing our knowledge on disease mechanisms and novel diagnostic tools for cancer.


application_id: 9096147
project_number: 4P30GM106396-04
project_title: ADMINISTRATIVE CORE
administering_ic: NIGMS
award_notice_date: 2016-07-28
opportunity_number: PAR-10-196
application_type: 4
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8526
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
PROJECT SUMMARY (See instructions): The Administrative Core (Core A) will be responsible for the day-to-day operation of the MT COBRE program. The overall goal of the Phase 111 application of the Molecular Targets COBRE (MT COBRE) is to ensure that the novel targets and compounds which have been identified by MT COBRE faculty are translated to pivotal human clinical trials. Under Dr. Miller's direction Core A will provide budgetary management core oversight manage the Pilot Grant Program and monitor progress of the MT COBRE faculty. The MT COBRE Administrative Assistant and the Program Coordinator will report to the MT COBRE PI and co-Director through this core. The Administrative Core will be responsible for organizing all committee meetings including those of the Steering Committee the Internal Advisory Committee and the External Advisory Committee. It will provide regular evaluations of research core function and fiscal status. Core A also will provide the requisite reports to the NIH Program administration on an annual basis. During the first ten years of MT COBRE funding. Core A has provided very important support to all of the MT COBRE faculty and has played an important role in the overall success of the program. This core will assume an even more important role during Phase III of the COBRE.

project_terms:
Advisory Committees;Antineoplastic Agents;Area;Cancer Center;Centers of Research Excellence;Clinical Trials;Core Facility;Ensure;Evaluation Research;Faculty;Funding;Goals;Grant;Growth;Human;Individual;Instruction;Laboratories;Leadership;Mentors;Molecular Target;Monitor;Phase;Physicians;Pilot Projects;Play;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Role;Scientist;Structure;Testing;Therapeutic;Training;Translating;Translational Research;United States National Institutes of Health;Universities;base;design;drug development;medical schools;meetings;member;novel;oncology;operation;programs;success;tumor metabolism

public_health_relevance:
RELEVANCE (See instructions): Cancer metabolism and cancer drug development are currently very important areas of research. The MT COBRE program has trained leaders in this area; the funding of Phase III will ensure the continued success and growth of the JGBCC core facilities and thus it's faculty and this program.


application_id: 9096136
project_number: 4P30GM106396-04
project_title: Molecular Targets Phase III CoBRE
administering_ic: NIGMS
award_notice_date: 2016-07-28
opportunity_number: PAR-10-196
application_type: 4
activity_code: P30
ic: GM
serial_number: 106396
program_official: LIU, YANPING
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: ZGM1-TWD-C(C3)
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): The Molecular Targets Center of Biomedical Research Excellence (MT COBRE) at the University of Louisville and the James Graham Brown Cancer Center has successful supported the early career of fourteen junior faculty members during its Phase I and il funding periods. The current application reflects the maturation of the Molecular Targets Program and its faculty. The overall goal of the Phase III application of the Molecular Targets COBRE will be to ensure that the novel targets and compounds which have been identified by MT COBRE faculty are translated to pivotal human clinical trials. Several strengths have enhanced the success of this program including: 1) Stability of program leadership; 2) Successful retention of all fourteen faculty members; 3) Institutional support for the program totaling over $30M; and 4) Creation of a University of Louisville-owned company dedicated to translating important discoveries of MT COBRE investigators. The ability of MT COBRE faculty to test their novel compounds in humans will distinguish this program from similar programs at other institutions.' To this end the MT COBRE has supported the development of a unique translational research infrastructure which has enabled the characterization of more than 30 novel targets. The Phase III application will support four closely
integrated core facilities which will support this goal; 1) Microarray Core; 2) Molecular Modeling Core; 3) NMR/Metabolomic Core and 4) Animal Model Core. Additionally the James Graham Brown Cancer Center has created complementary research cores which will be available to MT Program members during the Phase III component of the program including the Biostatistics Core Clinical Trials Office Biophysical Cancer Core Cell Sorting and Flow Cytometry Core. The MT COBRE administration will continue to provide intensive support for development of the fourteen faculty members many of whom have assumed leadership roles within the Cancer Center and University. The robust translational research infrastructure at the James Graham Brown Cancer Center and University of Louisville will ensure the success and sustainability of this unique program.

project_terms:
Accounting;Animal Model;Antineoplastic Agents;Area;Biostatistics Core;Cancer Center;Cell Separation;Centers of Research Excellence;Clinical Trials;Core Facility;Development;Ensure;Faculty;Flow Cytometry;Funding;Goals;Growth;Human;Institution;Leadership;Malignant Neoplasms;Molecular Models;Molecular Target;Phase;Research;Research Infrastructure;Research Personnel;Role;Testing;Training;Translating;Translational Research;United States National Institutes of Health;Universities;career;drug development;drug discovery;inhibitor/antagonist;member;metabolomics;molecular modeling;novel;novel therapeutics;pre-clinical;programs;public health relevance;success;targeted cancer therapy;tumor metabolism

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cancer metabolism and cancer drug development are currently very important areas of research. The MT COBRE program has trained leaders in this area; the funding of Phase III will ensure the continued success and growth of the core facilities and this program.


application_id: 9095167
project_number: 5U19AI113182-03
project_title: Project 3: PREVENT: A first-in-human clinical trial of Griffithsin an HIV entry
administering_ic: NIAID
award_notice_date: 2016-05-20
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6667
contact_pi_person_id: 7904401
contact_pi: MCGOWAN, IAN MICHAEL
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The overarching goal of the PREVENT Program is to develop a Griffithsin (GRFT) rectal gel that could be used prior to receptive anal intercourse (RAI) to reduce the risk of HIV infection by men who have sex with men (MSM). Project 3 will conduct a randomized placebo-controlled pre-Phase 1 human study to measure GRFT safety pharmacokinetics (PK) and pharmacodynamics (PD). We will recruit 18 healthy men to participate in a prospective trial to evaluate GRFT carbopol gel versus a matched placebo in a 2:1 randomization design. The study will address traditional product safety and PK parameters but we will also evaluate the effect of the product on adaptive immunity to GRFT by conducting a three stage study. The first stage will involve a single drug exposure. In Stages 2 and 3 men will receive 5 doses of gel product on consecutive days separated by a two week washout period. Rectal biopsies and other samples taken at baseline and during Stages 1-3 will be used to characterize mucosal responses to GRFT including enumeration of HIV target cells and detection of representative HIV receptors and epithelial junction proteins in the rectumby immunohistochemistry and flow cytometry. The biopsies will also be used for a PD assessment by ex vivo challenge of the tissue with HIV-1. Additionally we will employ a systems biology approach including transcriptomics proteomics and microbiome analysis to analyze the global impact of GRFT treatment on the mucosal environment in the rectum.

project_terms:
AIDS prevention;Address;Affinity;Animals;Antigens;Antiviral Agents;Anus;Awareness;Binding;Biopsy;Carbopol;Cell surface;Cells;Clinical Trials;Community Health;Data;Data Set;Detection;Dimensions;Dose;Drug Exposure;Drug Kinetics;Environment;Epithelial;Epithelial Cells;Exposure to;Flow Cytometry;Formulation;Gel;Gene Expression;Goals;HIV;HIV Entry Inhibitors;HIV Infections;HIV Receptors;HIV-1;HIV-2;Health;Hepatitis C virus;Human;Human Development;Immune;Immune response;Immunohistochemistry;In Vitro;Incidence;Inflammatory;Laboratories;Laboratory Animals;Lectin;Link;Lymphocyte;Measures;Metagenomics;Mucous Membrane;Mus;Natural Immunity;Oryctolagus cuniculus;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Phase;Phase I Clinical Trials;Placebo Control;Placebos;Plants;Polysaccharides;Prevention;Proteins;Proteomics;Randomized;Recruitment Activity;Rectum;Risk;Safety;Sampling;Simplexvirus;Staging;Structure;Surface;Systems Biology;T-Lymphocyte;Techniques;Tissues;Toxic effect;Vagina;Viral;adaptive immunity;base;crosslink;cytokine;design;healthy volunteer;human study;immunotoxicity;inhibitor/antagonist;men;men who have sex with men;microbial community;microbicide;microbiome;microbiota;novel;preclinical safety;prevent;programs;prospective;rRNA Genes;rectal;rectal microbicide;response;transcriptomics;transmission process;trial design;volunteer

public_health_relevance:
There is now evidence that rectal microbicides based on entry inhibitors can successfully block HIV transmission in high incidence settings and provide an invaluable addition to HIV prevention packages. This project describes the initial human development of a new anti-HIV rectal microbicide griffithsin (GRFT). If GRFT were shown to be effective it would have significant advantages over current microbicides.


application_id: 9095165
project_number: 5U19AI113182-03
project_title: Project 1: PREVENT Program Critical Path Project
administering_ic: NIAID
award_notice_date: 2016-05-20
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6665
contact_pi_person_id: 8752851
contact_pi: TUSE, DANIEL
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The overall goal of the Critical Path Project ("CPP"; Project 1) is to coordinate cGMP- compliant Drug Substance and Drug Product manufacture and release manage preclinical safety and efficacy studies and develop and integrate regulatory documents for submission of an Investigational New Drug (IND) application to US Food and Drug Administration (FDA) in support of an investigative clinical trial. Project 1 will establish the manufacturing methodology for the new product and help define an accelerated development path towards demonstration of clinical efficacy and product licensure. The novel active pharmaceutical ingredient (API) of our microbicide is Griffithsin (GRFT) a marine algal natural protein for which we have developed and scaled an efficient recombinant manufacturing process. GRFT is the most potent HIV-1 entry inhibitor known and also has high activity against other viruses that may be co-transmitted with HIV such as HSV-2. Through our collaborators in the PREVENT Program we have produced more than 200 g of GRFT for research use and developed effective and stable microbicide gel dosage forms. These prototype gels have been evaluated for initial safety in an ex vivo human explant system physicochemical stability and API release characteristics with very encouraging results. In Aim 1 of this Project we will apply methods we have successfully used to date to further optimize the API manufacturing process for maximum yield and recovery. The manufacturing process will be brought to compliance with FDA cGMP guidelines together with supporting documentation. Compliant API will be used to cGMP manufacture the rectal gel final dosage form optimized in Core B. In Aim 2 the safety and tolerability of the rectal gel product will be determined in regulation-compliant toxicology in 3 animal species with endpoints to include topical and systemic safety tolerability irritation sensitivity and immunotoxicity. Preliminary Chemistry Manufacturing and Controls (CMC) and safety information along with a draft clinical Protocol will be discussed with FDA in a pre-IND meeting. Agency feedback will assist us in finalizing an IND application activation of which by FDA will allow us to initiate a first-in-humans clinical trial of the GRFT microbicide in Project 3.

project_terms:
AIDS prevention;Animals;Biological Assay;Carbopol;Characteristics;Chemistry;Clinic;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Critical Pathways;Cyclic GMP;Development;Documentation;Dosage Forms;Drug Packaging;Ensure;Feedback;Formulation;Gel;Goals;Guidelines;HIV;HIV vaccine;HIV-1;Human;Human Herpesvirus 2;Investigational Drugs;Investigational New Drug Application;Licensure;Marines;Marketing;Methodology;Methods;Mus;Nicotiana;Oryctolagus cuniculus;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Plants;Prevention;Production;Proteins;Published Comment;Rattus;Recombinants;Recovery;Regulation;Research;Risk;Rodent;Route;Safety;Skin;Suggestion;System;Toxicology;Training;United States Food and Drug Administration;Vagina;Viral;Virus;Work;base;cGMP production;clinical efficacy;genotoxicity;immunotoxicity;in vivo;inhibitor/antagonist;irritation;manufacturing process;meetings;microbial;microbicide;novel;pre-clinical;preclinical efficacy;preclinical safety;preclinical study;programs;prototype;rectal;rectal microbicide;safety study;transmission process

public_health_relevance:
Without a preventative HIV vaccine microbicides may offer a powerful option for the prevention of HIV transmission through the rectal and vaginal routes. This Project manages the key development tasks to bring to the clinic a novel microbicide candidate protein griffithsin which could be economically manufactured at a market-relevant scale using our plant-based production system.


application_id: 9095164
project_number: 5U19AI113182-03
project_title: Core D: PREVENT Program Regulatory Affairs Core
administering_ic: NIAID
award_notice_date: 2016-05-20
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6664
contact_pi_person_id: 7904401
contact_pi: MCGOWAN, IAN MICHAEL
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The purpose of Core D is to provide an infrastructure of regulatory and technical expertise to maintain and manage consistent compliance with the regulatory requirements for all projects in the PREVENT Program. The Core includes two separate but complementary components: (i) oversight of the preclinical work required to support a successful IND including interactions with the FDA and (ii) management and oversight of regulatory compliance training and implementation of a pre-Phase 1 clinical trial. The Core will manage track develop and provide coordinated responses to all regulatory submissions and Agency interactions. This will include the transition from pre-GMP to cGMP drug substance and drug product manufacture pilot and GLP preclinical toxicology strategic interactions with external regulatory agencies and IND development and submissions with a focus on regulatory training and education and the goal of standardizing the Program's regulatory practices. The Core will also provide an overall Quality Management Plan and implement and monitor quality control and quality assurance activities as needed throughout all program projects and cores. The Core will coordinate and direct all required self-monitoring activities and will serve as a central document control repository.

project_terms:
Accelerometer;Blinded;Clinical;Clinical Data;Clinical Trials;Code;Cyclic GMP;Data;Development;Drug Kinetics;Ensure;Gel;Goals;Housing;Human;Monitor;Peer Review;Pharmaceutical Preparations;Pharmacodynamics;Phase I Clinical Trials;Practice Management;Prevention;Process;Publications;Quality Control;Randomized;Regulation;Regulatory Affairs;Reporting;Research;Research Infrastructure;Sampling;Site;Systems Biology;Technical Expertise;Time;Toxicology;Training;Training and Education;Viral;Work;base;innovation;microbicide;pre-clinical;programs;quality assurance;rectal;rectal microbicide;repository;response;symposium;volunteer

public_health_relevance:
PREVENT Program Regulatory Affairs Core (Core D) will ensure that the overall PREVENT program complies with regulatory requirements. The core will oversee activities relating to product manufacture regulations as well as clinical trial regulations.


application_id: 9095163
project_number: 5U19AI113182-03
project_title: Core C: PREVENT Program Pharmacokinetics and Pharmacodynamics Services Core
administering_ic: NIAID
award_notice_date: 2016-05-20
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6663
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The objective of the Pharmacokinetics and Pharmacodynamics (PK/PD) Services Core will be to provide centralized support for the PK and key PD analyses common to preclinical macaque studies in Project 2 and human clinical studies in Project 3 thereby ensuring Program's research integrity and comparability between the preclinical and clinical studies proposed. To this end we will provide the following functions. (1) We will validate the quality of a griffithsin (GRFT) reference standard. A series of biochemical biophysical and virological assays will be used to validate the quality of GRFT. (2) We will develop an immunoassay to validate the potency of GLP/GMP-manufactured GRFT. Upon validation of the assay at OCRP its standard operating procedure will be transferred to Project 1 and Core B. (3) We will detect and quantify GRFT active pharmaceutical ingredient (API) and GRFT-binding antibodies in biological fluids to support PK/PD analysis in Projects 2 and 3. In addition to conventional methods based on enzyme-linked immunosorbent assays we will develop surface plasmon resonance-based analytical methods to detect low-affinity rapidly dissociating antibodies. As part of PK assessment we will use HIV-1 neutralization and cell-cell fusion assays to measure the anti-HIV-1 capacity of rectal fluid samples. (4) We will analyze the impact of GRFT gel treatment on the mucosal environment to support in vivo safety assessment. To this end we will employ a systems biology approach to comprehensively reveal the changes in the mucosal environment that may occur upon rectal administration of GRFT and GRFT combination gels. The induction of innate and adaptive immune responses in the mucosal and systemic immune compartments will be assessed using proteomic techniques. We will also use highly sensitive immunohistochemistry techniques to compare the number and location of HIV target cells and epithelial junction proteins in rectal tissue. Additionally the structure of rectal microbiota throughout the course of GRFT and combination gel treatment will be monitored by barcoded 16S rRNA genes sequencing to reveal the effect of microbicides formulation on the taxonomic structure of the rectal microbiota.

project_terms:
Adverse effects;Affinity;Anti-HIV Agents;Antibodies;Binding;Biochemical;Biological;Biological Assay;Biological Markers;Blood specimen;Body Fluids;Cell Line;Cell fusion;Cells;Clinical Research;Complement;Complex;Cyclic GMP;Detection;Development;Drug Kinetics;Ensure;Environment;Enzyme-Linked Immunosorbent Assay;Epithelial Cell Junction;Evaluation;Fluorescence;Formulation;Gel;Gene Expression Profiling;Giant Cells;Glycoproteins;HIV;HIV Envelope Protein gp120;HIV-1;Hela Cells;High Pressure Liquid Chromatography;Histopathology;Human;Human Herpesvirus 2;IgE;Immune;Immunoassay;Immunoblotting;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Immunoglobulins;Immunohistochemistry;Lead;Liquid substance;Location;Macaca;Macaca mulatta;Measures;Methods;Molecular Sieve Chromatography;Monitor;Mucous Membrane;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Prevention;Procedures;Proteins;Proteomics;Quality Control;Reagent;Rectal Administration;Reference Standards;Reporter Genes;Research;Safety;Sampling;Series;Services;Structure;Surface Plasmon Resonance;Systems Biology;Techniques;Technology Transfer;Testing;Tissues;Toxicology;Validation;Viral;adaptive immunity;analytical method;base;immunogenicity;in vivo;microbicide;microbiota;pre-clinical;pre-clinical research;preclinical study;programs;rRNA Genes;rectal;rectal microbicide

public_health_relevance:
Pharmacokinetics and Pharmacodynamics Services Core will facilitate preclinical and clinical research by developing and providing key assays and reagents to other components of the U19 PREVENT Program Project investigating the potent anti-HIV protein griffithsin as a candidate rectal microbicide.


application_id: 9095162
project_number: 5U19AI113182-03
project_title: Core B: PREVENT Product Development Core
administering_ic: NIAID
award_notice_date: 2016-05-20
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6662
contact_pi_person_id: 6194125
contact_pi: ROHAN, LISA CENCIA
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
Given the significant anatomical and physiological differences in the rectal and vaginal compartments it is essential to design rectal specific microbicide products to effectively inhibit rectal transmission of HIV. The overall goal of the Product Development Core (Core B) is in the provision of formulated Griffithsin (GRFT) gel products and quality physiochemical safety and efficacy assessments for these products. Specifically Core C will provide preformulation data formulation development efforts and formulation assessment evaluations in support of Projects 1 2 and 3 as well as Cores C and D. Formulation strategies within the scope of Core activities will be initiated utilizing knowledge obtained from previously developed rectal and vaginal GRFT gel products. Product attributes will be modified to obtain defined target specifications suitable for rectal application. The rectal specific GRFT product will be tested for safety and efficacy using an excised mucosal tissue explant model. A final formulation will be chosen based on successful achievement of defined target product profiles. Once the newly developed rectal GRFT formulation is obtained it will be scaled up and manufactured to support GLP animal safety testing studies and other preclinical assessments planned within Projects 1 and 2. Manufacture of GMP quality material will be achieved through a contract research organization within Project 1. Core B will be responsible for methods transfer provide assistance with development of batch records generated assist in protocol development for product assessment methods established for GMP product release and review stability results obtained. Additionally Core B will design a rectal specific GRFT combination product with enhanced potency as a second generation product. Efforts toward this end will be initiated through application of a screening algorithm to identify the most effective combination. Lead secondary antiretroviral candidates include tenofovir (TFV) and dapivirine(DPV). TFV and DPV are the lead ARV candidates currently being evaluated in the clinic. Quantitative assays to support formulation efforts have been developed in the laboratory for GRFT TFV and Dapivirine. This Core plays a critical role in the activities described within the PREVENT Program. The products and testing parameters developed within this core will be utilized by all projects and cores within the program.

project_terms:
Achievement;Algorithms;Animals;Anti-Retroviral Agents;Biological Assay;Carbopol;Characteristics;Chemicals;Chemistry;Clinic;Clinical;Clinical Research;Clinical Trials;Critical Pathways;Cyclic GMP;Data;Development;Documentation;Dose;Drug Combinations;Drug Kinetics;Ensure;Evaluation;Formulation;Gel;Generations;Goals;HIV;Human;Investigational New Drug Application;Knowledge;Laboratories;Lead;Macaca;Methods;Modeling;Modification;Mucous Membrane;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Placebos;Play;Preparation;Prevention;Procedures;Production;Property;Proteins;Records;Rectal Administration;Regulation;Regulatory Affairs;Research Contracts;Role;Safety;Series;TMC120-R147681;Technology Transfer;Tenofovir;Testing;Toxic effect;Toxicology;Vagina;Vaginal Gel;Viral;analytical method;base;chemical stability;condoms;design;dosage;immunogenicity;manufacturing scale-up;microbicide;oxidation;packaging material;pre-clinical;preclinical efficacy;preclinical safety;preclinical study;product development;programs;protocol development;prototype;rectal;rectal microbicide;safety testing;screening;transmission process

public_health_relevance:
Product Development Core (Core B) will provide formulation development focused on the development of the anti-HIV protein griffithsin single entity and combination products. This Core will also conduct activities to ensure the safety of gels advancing to clinical trials.


application_id: 9095160
project_number: 5U19AI113182-03
project_title: Core A: PREVENT Program Administrative Core
administering_ic: NIAID
award_notice_date: 2016-05-20
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6661
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
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
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The overall objective of the PREVENT Program is to advance into clinical trials a candidate microbicide gel containing griffithsin (GRFT) that is designed to prevent rectal transmission of HIV-1. The primary responsibility of the Administrative Core (Core A) is to monitor direct and coordinate activities of the three research projects and three scientific cores to ensure that this objective is achieved efficiently as quickly as possible and in compliance with regulatory and sponsor requirements. The overarching goal of Core A is to provide scientific support to the PREVENT program's projects and cores to enable progression into the PREVENT clinical trial. Specific Aim 1 is to ensure effective PREVENT Program leadership through coordinated efforts of a Steering Committee (SC). Aim 2 is to provide administrative support for the effective functioning of the entire GRFT PREVENT program. Aim 3 is to provide centralized fiscal management of projects and cores and Aim 4 is to provide an internal structure for both internal and external review of scientific progress.

project_terms:
Archives;Award;Biometry;Calendar;Clinic;Clinical Trials;Collaborations;Communication;Consensus;Consult;Decision Making;Ensure;Experimental Designs;Gel;Goals;Grant;HIV-1;Information Dissemination;Leadership;Methods;Monitor;Online Systems;Paper;Prevention;Preventive vaccine;Problem Solving;Progress Reports;Proteins;Protocols documentation;Research Project Grants;Secure;Sexual Transmission;Site;Structure;TimeLine;United States National Institutes of Health;Universities;Viral;Work;base;condoms;design;meetings;microbicide;novel;posters;prevent;programs;rectal;rectal microbicide;transmission process

public_health_relevance:
In the absence of a preventative vaccine microbicides offer an alternative to condoms as a feasible method for prevention of HIV-1 sexual transmission. This Core manages the key administrative and fiscal tasks to bring to the clinic a novel candidate microbicide gel containing the potent anti-HIV01 protein griffithsin.


application_id: 9095121
project_number: 5F31AI120653-02
project_title: Fusion protein TM-TM interactions: Modulation of pre-fusion protein stability
administering_ic: NIAID
award_notice_date: 2016-04-13
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: AI
serial_number: 120653
program_official: REPIK, PATRICIA M
project_start_date: 2015-05-15
project_end_date: 2017-05-14
study_section: Special Emphasis Panel[ZRG1-F13-C(20)L]
contact_pi_person_id: 12308147
contact_pi: WEBB, STACY RENEE
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): Recent studies have altered the perception of transmembrane domains (TMDs) from hydrophobic anchors to important factors in protein function including protein oligomerization cell signaling and regulation of channel function (cite). Despite these advancements the role of TMDs in viral glycoprotein stability and function remains poorly understood. Previous studies from our lab utilized sedimentation equilibrium (SE) ultracentrifugation analysis to demonstrate that the isolated TMD of several viral glycoproteins associate in a monomer-trimer equilibrium. Functional analysis of mutations in the TMD of the full length Hendra virus F protein also revealed altered expression levels and fusion activity. These studies implicate TM-TM interactions in regulation of F protein folding and function. Preliminary data from our lab identified the presence of an L/I zipper within the TMD of HeV F that continues in frame with the L/I zipper of the upstream heptad repeat domain B (HRB). Using site directed mutagenesis I demonstrated that by replacing the four L/I residues that continue into the TMD with alanine TM-TM association is dramatically reduced as determined by analytical ultracentrifugation. Introducing these mutations into the full length F protein I also found that F protein mediated membrane fusion was dramatically reduced. Further characterization of the TMD including features of the environment important for association will provide critical information regarding F protein function and therefore provide insights into viral membrane fusion. The overall hypothesis of this proposal is that TM-TM association and fusion protein stability are affected by the lipid environment of the viral particl and also specific residues within the TMD therefore making TMDs a potential target for antiviral therapeutics. To test this important hypothesis we will define the role of key residues in HeV F protein TM-TM interactions and pre-fusion stability by determining the effect of TMD mutations on TM-TM association in an E. coli reporter system GALLEX and also assess the effect the mutations have on the full length fusion protein in eukaryotic cells. Also I will determine whethe the L/I zipper is important for TM-TM association in other viral fusion proteins by analyzing the L/I zipper present in the TMD of Ebola GP and SARS CoV S two other type I fusion proteins. Finally since TM-TM interactions take place in the complex environment of lipid bilayers I will also dissect the role of the lipid environment in pre-fusion stability and TM-TM association. These experiments will utilize virus like particles which will enable for modulation of lipid content. Overall these important experiments will provide new insights into the important field of
TMDS association and enhance our understanding of F protein stability.

project_terms:
Affect;Alanine;Antiviral Agents;Chimeric Proteins;Cholesterol;Complex;Data;Development;Ebola virus;Environment;Equilibrium;Escherichia coli;Eukaryotic Cell;Glycoproteins;Hendra Virus;Human Metapneumovirus;Length;Lipid Bilayers;Lipids;Mediating;Membrane Fusion;Membrane Glycoproteins;Molecular Conformation;Mutation;Mutation Analysis;Perception;Point Mutation;Proteins;Regulation;Reporter;Research;Role;SARS coronavirus;Scanning;Sequence Analysis;Signal Transduction;Site-Directed Mutagenesis;Sphingolipids;Surface;System;Testing;Therapeutic;Time;Transmembrane Domain;Ultracentrifugation;Viral;Viral Fusion Proteins;Virus-like particle;analytical ultracentrifugation;insight;monomer;mutant;new therapeutic target;particle;protein S precursor;protein folding;protein function;public health relevance;research study;sedimentation equilibrium

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The project outlined in this proposal will further our understanding of TM-TM interactions in viral surface glycoproteins providing a greater understanding of viral entry. This research will help to elucidate details regarding fusion protein
stability and function and potentially provide new therapeutic targets for the development of antivirals.


application_id: 9094702
project_number: 4U10NS058967-10
project_title: UK NETT Clinical Site Hub
administering_ic: NINDS
award_notice_date: 2016-07-07
opportunity_number: PAR-11-342
application_type: 4
activity_code: U10
ic: NS
serial_number: 058967
program_official: JANIS, SCOTT
project_start_date: 2007-05-03
project_end_date: 2018-05-31
study_section: ZNS1-SRB-N(01)
contact_pi_person_id: 8686194
contact_pi: HUMPHRIES, ROGER LOYD
other_pis: Not Applicable
congressional_district: 06
department: EMERGENCY 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal describes the re-establishment of a Neurological Emergencies Treatment Trials (NETT) Network Clinical Site Hub at the University of Kentucky Chandler Medical Center (UKCMC) in Lexington Kentucky in response to NIH/NINDS PAR-11-342. The overall goal of this proposal is to identify UKCMC as an academic medical facility with regional affiliate partners adept in "the evaluation of treatments for patiens with a broad spectrum of neurological emergencies." The NETT Clinical Hub Site at UKCMC (UK NETT) has been a vigorous participant in the NETT Network since its competitive selection as one of the original 17 Network sites in 2007. During the past 4 years as a participating Clinical Hub Site UK NETT has enrolled more than 50 subjects in the Phase 111 clinical trials undertaken within the NETT Network to include RAMPART (midazolam v. lorazepam in status epilepticus) ALIAS Part 2 (albumin v. placebo in acute ischemic stroke) POINT (clopidogrel loading for stroke prevention after transient ischemic attack) and ProTECT (progesterone v. placebo in traumatic brain injury). Emergency Medicine is well represented within this venture as the original and proposed UK NETT are based within the Department of Emergency Medicine at UKCMC. UK NETT is founded upon an intra-institutional collaboration that extends beyond Emergency Medicine to include physician faculty members in the Departments of Neurology Neurosurgery Surgery/Trauma Surgery and Anesthesiology/Intensive Care Medicine. Regional affiliate medical care facilities aligned with UK NETT include "spoke" community hospitals located within Kentucky. The following Specific Aims are proposed: 1) To demonstrate the existence of an infrastructure for high-volume subject recruitment in "large simple" clinical trials performed in acute-onset neurological disorders and 2) To demonstrate experience in successfully conducting clinical trials in acute-onset neurological disorders requiring Exception from Informed Consent as regulated by the United States Food & Drug Administration.

project_terms:
Accident and Emergency department;Acute;Affect;Air;Albumins;Ambulances;American;Anesthesiology;Area;Beds;Brain;Caring;Cause of Death;Clinical;Clinical Research;Clinical Trials;Collaborations;Communities;Community Hospitals;Conduct Clinical Trials;Disease;Emergency Medicine;Emergency treatment;Enrollment;Evaluation;Faculty;Goals;Grant;Healthcare;Hospitals;Human;Individual;Informed Consent;Intensive Care;Internet;Ischemic Stroke;Kentucky;Lorazepam;Medical;Medical center;Medicine;Midazolam;Modeling;National Institute of Neurological Disorders and Stroke;Nervous system structure;Network-based;Neurological emergencies;Neurology;Operative Surgical Procedures;Participant;Patients;Pharmacists;Phase;Phase III Clinical Trials;Physicians;Placebos;Positioning Attribute;Progesterone;Progress Reports;Public Health;Recruitment Activity;Regulation;Research;Research Infrastructure;Rural;Seizures;Services;Site;Source;Speed;Spinal cord injury;Status Epilepticus;Stream;Stroke prevention;Telecommunications;Transient Ischemic Attack;Trauma;Traumatic Brain Injury;United States Dept. of Health and Human Services;United States Food and Drug Administration;United States National Institutes of Health;Universities;University resources;Urban Population;base;clinical research site;clopidogrel;disability;experience;high risk;meetings;member;nervous system disorder;neurosurgery;programs;response;square foot;stroke;success;support network;trauma centers;treatment trial

public_health_relevance:
The relevance of this proposal for public health is to identify the University of Kentucky Chandler Medical Center in Lexington Kentucky as a regional center for clinical research in acute illnesses affecting the human nervous system. These conditions include stroke seizures traumatic brain or spinal cord injury and other disorders among the most common causes of death and serious disability affecting American citizens.


application_id: 9094580
project_number: 4P50DA005312-26
project_title: Examining Urgency from Neurobiology to Prevention
administering_ic: NIDA
award_notice_date: 2016-05-25
opportunity_number: PAR-10-189
application_type: 4
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2019-06-30
study_section: ZDA1-EXL-T
subproject_number: 6590
contact_pi_person_id: 3122080
contact_pi: LYNAM, DONALD R
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: 2016-07-01
project_abstract:
Impulsive behavior is an important contributor to substance misuse which is prevalent in college samples.Our center (CDART) has identified four distinct personality traits that underlie impulsive behaviors: NegativeUrgency (NU) lack of Premeditation (PRE) lack of Perseverance (PSV) and Sensation Seeking (SS). Ourprevious work clarified the roles of SS and PRE in substance misuse in the college population. In our morerecent work NU has emerged as an important and independent contributor to substance misuse. Even aftercontrolling for SS and PRE NU is related to the onset and escalation of substance misuse and other riskybehaviors and the relation between NU and alcohol use is mediated through different mechanisms than therelations for PRE and SS. Thus our previous work clearly shows that understanding NU is criticallyImportant to the prevention of substance misuse in college populations. The four proposed studies will use arange of methods to investigate the nature of NU and the mechanisms through which it exerts its effects.Study 1 will identify underlying biological substrates of NU using fMRI. It is predicted that regions in theprefrontal cortex associated with inhibitory control will show less activation in high NU participants whenparticipants are experiencing negative affect. Study 2 will identify the affective contexts and responsecharacteristics most important to NU. It is predicted that affect will be more important to NU than to otherimpulsivity traits and that NU will manifest in impulsive behavior on tasks that include prepotent responsesand/or tasks in which an impulsive response is negatively reinforced. Study 3 will examine the interactionsamong impulsivity traits affective contexts and interpersonal contexts in predicting impulsive behavior indaily life. It is predicted that NU will be related to impulsive behavior when high NU participants are under theinfluence of negative mood. Other impulsivity traits like SS may be more responsive to interpersonalcontexts. Study 4 will test whether an intervention designed to help high NU participants respond moreadaptively to their negative affect can reduce future impulsive behavior. It is predicted that mindfulnesstraining will reduce impulsive behaviors among high NU individuals but not among high SS individuals.RELEVANCE (See instructions):Prevention of substance misuse in college samples is important because of the associated public healthrisks including death injury long-term illness and disability. Negative urgency is a strong but understudiedpredictor of substance misuse. The proposed studies will contribute to prevention research by clarifying thenature of negative urgency and the mechanisms through which it exerts its effects on substance misuse.

project_terms:
Address;Adolescent;Affect;Affective;Aggressive behavior;Alcohol consumption;Alcohol or Other Drugs use;Amygdaloid structure;Attention deficit hyperactivity disorder;Biological;Borderline Personality Disorder;Boredom;Cessation of life;Characteristics;Child;Clinical;Conduct Disorder;Consensus;Crime;Dimensions;Disinhibition;Drug abuse;Drug usage;Eating Disorders;Esthesia;Functional Magnetic Resonance Imaging;Future;Impulsive Behavior;Impulsivity;Individual;Injury;Instruction;Knowledge;Laboratories;Life;Mediating;Methodology;Methods;Modeling;Nature;Neurobiology;Participant;Personality Traits;Population;Predisposition;Prefrontal Cortex;Prevention;Prevention Research;Preventive;Preventive Intervention;Principal Investigator;Problem behavior;Process;Public Health;Regulation;Research;Rewards;Risk;Risk Behaviors;Risk Factors;Risk-Taking;Role;Running;Sampling;Specific qualifier value;Stimulus;Substance Use Disorder;Syndrome;Testing;Thinking;Training;Translational Research;Work;anti social;antisocial behavior;base;behavioral response;college;disability;distraction;experience;high risk drinking;high risk sexual behavior;improved;intimate partner violence;marijuana use;mindfulness;negative affect;negative mood;neural circuit;operation;preference;psychological stressor;response;substance misuse;substance misuse prevention;theories;therapy design;trait;trait impulsivity;violent crime;willingness


application_id: 9094579
project_number: 4P50DA005312-26
project_title: Indivicual Differences in Drug abuse Liability
administering_ic: NIDA
award_notice_date: 2016-05-25
opportunity_number: PAR-10-189
application_type: 4
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2019-06-30
study_section: ZDA1-EXL-T
subproject_number: 6589
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS H.
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: 2016-07-01
project_abstract:
Prevention investigators in our Center and elsewhere have demonstrated that drug abuse preventionefficacy can be significantly enhanced by targeting individuals who are most vulnerable to developingproblems and tailoring message content and format based on the characteristics of these individuals. Ourprevious work focused on drug use initiation and identified behavioral mechanisms (neurobehavioralresponse to reinforcing novel and emotional stimuli) whereby the sensation seeking dimension of impulsivityis associated with vulnerability to drug use initiation and high sensation-value contexts enhance the efficacyof prevention interventions designed to reduce drug use initiation. Further development of laboratory modelsto identify individuals who are vulnerable to drug use escalation and development of associated problemsand identifying the characteristics of these individuals that predispose them to vulnerability and/or influencethe efficacy of targeted intervention materials is of critical importance for informing and advancing the field ofdrug abuse prevention. This application proposes five years of research to continue laboratory investigationsof individual differences associated with drug use escalation and associated exposure to heavy drug use.Growing evidence suggests that vulnerability to drug-use escalation is associated with self-controlmechanisms. A multidisciplimary approach combining personality measurement with laboratory abuseliability assessment behavioral inhibition task performance and brain imaging methodologies will be used toexamine impulsivity among matched groups of tobacco and marijuana users who have either maintainedstable patterns of intermittent/light use (escalation resistant) or who have escalated to heavy use with andwithout extended histories of heavy use (escalation; escalation + extended drug exposure) to test thehypothesis that drug use escalation is associated with inhibitory neurobehavioral dimensions of impulsivity.Knowledge of the association between component dimensions of impulsivity and drug-use escalation willenhance understanding of vulnerability to and consequences of drug use escalation and thus our ability todesign more efficacious tailored and targeted drug abuse prevention interventions.RELEVANCE (See instructions):Drug abuse prevention efficacy is improved by targeting at-risk individuals and tailoring interventions basedon the characteristics of those individuals. Impulsivity is closely linked with drug abuse vulnerability. Thisproject will support prevention science by identifying the neurobehavioral dimensions of impulsivity that areassociated with vulnerability to and adverse consequences of tobacco and marijuana use escalation.

project_terms:
Alcohols;Automobile Driving;Behavior;Behavioral;Behavioral Mechanisms;Behavioral inhibition;Brain imaging;Characteristics;Clinical;Dependence;Development;Dimensions;Disinhibition;Drug Exposure;Drug abuse;Drug usage;Drug user;Esthesia;Exposure to;Impairment;Impulsivity;Individual;Individual Differences;Instruction;Intervention;Investigation;Knowledge;Laboratories;Laboratory Study;Light;Link;Marijuana;Matched Group;Measurement;Mediating;Methodology;Modeling;Motivation;Nicotine;Pattern;Personality;Pharmaceutical Preparations;Prevention;Preventive Intervention;Process;Psychological reinforcement;Public Health;Recording of previous events;Research;Research Personnel;Resistance;Risk;Role;Science;Self Administration;Self-control as a personality trait;Staging;Task Performances;Testing;Tetrahydrocannabinol;Tobacco;Tobacco use;Translational Research;Vulnerable Populations;Work;adverse outcome;alcohol effect;alcohol measurement;base;behavioral impairment;design;drinking;drug abuse prevention;drug abuse vulnerability;drug reinforcement;drug use vulnerability;emotional stimulus;improved;laboratory development;marijuana use;marijuana user;neurobehavioral;novel;prevent;programs;response;success;therapy design;young adult


application_id: 9094578
project_number: 4P50DA005312-26
project_title: Individual Differences in Facets of impulsivity: An Animal Model
administering_ic: NIDA
award_notice_date: 2016-05-25
opportunity_number: PAR-10-189
application_type: 4
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2019-06-30
study_section: ZDA1-EXL-T
subproject_number: 6588
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
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: 2016-07-01
project_abstract:
The central theme of CDART is that multiple facets of impulsivity defined by the UPPS scale of Whitesideand Lynam (2001) are related to different paths to drug use and that these paths are associated withdifferent neurobiological mechanisms. To the extent that we can link specific behavioral tasks to thesedifferent self-report facets animal models can be used to identify critical neural mechanisms that undedie theassociation between risk-related facets and drug use. A detailed understanding of the mechanisms thatmediate the link between different facets of impulsivity and drug use will provide information about designingpreventive interventions that target these risk-related facets. The overall goal of this preclinical project is to test two overarching hypotheses: (1) individual differencesin the facets termed "urgency" "disinhibition" and "sensation seeking" are related most strongly to problemuse escalation and initiation respectively as operationally defined within an animal model of drug self-administration; and (2) individual differences in urgency disinhibition and sensation seeking are related moststrongly to differences in amygdala prefrontal cortex and nucleus accumbens respectively as measured byin vitro neurochemistry and in vivo electrophysiology. The specific aims are to: Aim 1: Develop an animal model of urgency using a task similar to that developed in humans. Aim 2: Determine if individual differences in urgency disinhibition and sensation seeking predict problemuse escalation and/or initiation of amphetamine self-administration respectively. Aim 3: Determine if individual differences in facets of impulsivity differentially predict the ability ofnondrug interventions to reduce use escalation and/or initiation of amphetamine self-administration. Aim 4: Determine if individual differences in these risk-related facets of impulsivity are related toalterations in monoamine transporter function in amygdala prefrontal cortex and/or nucleus accumbens. Aim 5: Determine if individual differences in these risk-related facets of impulsivity are related to alteredpatterns of neuronal activity in amygdala prefrontal cortex and/or nucleus accumbens.RELEVANCE (See instructions): Anti-drug preventive interventions may be most effective if they are designed to target those at highestnsk. The current project will explore the basic neurobehavioral mechanisms that mediate risk. The long-term goal is to translate these basic research findings into the design of targeted biologically-relevantpreventive interventions that can be evaluated in field studies.

project_terms:
Address;Adolescent and Young Adult;Alcohol or Other Drugs use;Amphetamines;Amygdaloid structure;Animal Model;Basic Science;Behavior;Behavioral;Biological;Brain;Cocaine;Disinhibition;Drug abuse;Drug usage;Electrophysiology (science);Esthesia;Exanthema;Failure;Goals;Human;Impulsivity;In Vitro;Individual Differences;Instruction;Intervention;Link;Measures;Mediating;Methylphenidate;Moods;Nicotine;Nucleus Accumbens;Patient Self-Report;Personality;Pharmaceutical Preparations;Population;Prefrontal Cortex;Preventive Intervention;Questionnaires;Rattus;Research Personnel;Risk;Self Administration;Staging;System;Testing;Translating;Translational Research;amphetamine use;base;design;discounting;field study;follow-up;human subject;in vivo;instrument;monoamine;neurobehavioral;neurobiological mechanism;neurochemistry;neuromechanism;neuronal patterning;non-drug;pre-clinical;preference;programs;research study


application_id: 9094577
project_number: 4P50DA005312-26
project_title: Training and Pilot Core
administering_ic: NIDA
award_notice_date: 2016-05-25
opportunity_number: PAR-10-189
application_type: 4
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2019-06-30
study_section: ZDA1-EXL-T
subproject_number: 6586
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
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: 2016-07-01
project_abstract:
The new Training and Pilot Core for the Center for Drug Abuse Research Translation (CDART) has thespecific goal of encouraging trainees to develop implement and evaluate evidence-based preventiveinterventions that rely on multi-disciplinary perspectives and research. The central theme of CDART is thatdifferent facets of impulsivity (urgency disinhibition and sensation seeking) are associated most strongly withdifferent phases of drug use/abuse (problem use escalation and initiation respectively). As a keycomponent of CDART this core will require trainees to build bridges that connect different areas of researchand translate basic research into prevention practice. Pilot investigators will be encouraged to design andimplement preventive interventions that fit within the CDART theme. Thus we will expand and formalize theroles of training and pilot project development through the following Specific Aims: 1) Provide the structureto train graduate students and postdoctoral scholars in translational research relevant to drug abuseprevention; 2) Promote and manage our pilot project program that introduces faculty and researchassociates to translational research relevant to drug abuse prevention and CDART's research mission; 3)Identify promising minority candidates for recruitment into the training and pilot project programs relevant todrug abuse prevention. As part of the approach pre- and post-doctoral trainees will be introduced to the fieldof drug abuse prevention with a special emphasis on translational work by attending and presenting inmonthly trainee data presentations attending seminars by researchers in drug abuse and retreats designedto "brainstorm" with CDART faculty about future research plans taking relevant topic-specific courses andethics in research training and attending informal seminars. The pilot program will prioritize eariy careerinvestigators and minority scholars for funding as well as more advanced faculty new to the drug abusefield. Proposals will be required to demonstrate the relevance of the project to the science and practice ofdrug abuse prevention. As a result CDART trainees and pilot project principal investigators will be preparedto take lead roles in bridging the gap between basic and applied researchers.RELEVANCE (See instructions):Prevention strategies are important for reducing the incidence of drug abuse. The Training and Pilot Core willwill require CDART trainees to build bridges connecting and translating basic reearch into preventionscience. As such the core will be instrumental in preparing trainees and fostering pilot project investigatorsto take leading roles in bridging the gap between basic and applied research in prevention science.

project_terms:
Applied Research;Area;Award;Basic Science;Budgets;Clinical Psychology;Conflict (Psychology);Data;Data Set;Development;Disinhibition;Drug abuse;Drug usage;Esthesia;Ethics;Faculty;Fostering;Funding;Goals;Grant;Health Communication;Impulsivity;Incidence;Instruction;Kentucky;Lead;Length;Minority;Mission;Neurosciences;Personality;Pharmacy facility;Phase;Pilot Projects;Postdoctoral Fellow;Prevention;Prevention strategy;Preventive Intervention;Principal Investigator;Psychology;Psychopharmacology;Research;Research Personnel;Research Training;Role;Science;Structure;Time;Training;Translating;Translational Research;United States National Institutes of Health;Universities;Work;career;design;drug abuse prevention;evidence base;faculty research;graduate student;medical specialties;minority investigator;pre-doctoral;programs;statistics;student training;success;theories;training project


application_id: 9094576
project_number: 4P50DA005312-26
project_title: Statistics and Psychomertrics Core
administering_ic: NIDA
award_notice_date: 2016-05-25
opportunity_number: PAR-10-189
application_type: 4
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2019-06-30
study_section: ZDA1-EXL-T
subproject_number: 6585
contact_pi_person_id: 8750849
contact_pi: CHARNIGO, RICHARD JOHN
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: 2016-07-01
project_abstract:
The new Statistics and Psychometrics Core (SPC) for the University of Kentucky's Center for Drug AbuseResearch Translation (CDART) grew out of demand for quantitative services provided previously in theAdministrative Core. The SPC will expand and formalize the roles of the statisticians and methodologistswith whom CDART investigators and graduate student / postdoctoral researcher trainees have collaboratedfor years. The functions fulfilled by these statisticians and methodologists will include: (i) consultation onstudy design and data analysis ranging from discussions at CDART committee and project meetings to one-on-one / small-group assistance provided in person and through electronic correspondence; (ii) directperformance of data analysis both cross-sectional and longitudinal that apply appropriate statisticalmethodology requiring special expertise in statistical computing or conversance with mathematicallytechnical concepts relevant to prevention scientists; (iii) co-authorship on manuscripts presenting newscientific findings entailing not only preparation of narrative for data analysis directly performed but alsobroader oversight of manuscript content to ensure lucidity and technical accuracy; (iv) outreach to the largerprevention psychological and neurobehavioral research communities through co-organization of aworkshop for a national audience and manuscripts acquainting investigators with state-of-the-artmethodology; (v) instruction to trainees on data analysis and statistical computing both through scheduledmethodology for one-on-one / small-group assistance provided in person and through electroniccorrespondence; and (vi) assistance in psychometric evaluation and development of measurementinstruments including both self-report questionnaires and behavioral tasks.RELEVANCE (See instructions):The Statistics and Psychometrics Core will provide quantitative expertise to center investigators in order tofulfill it's basic mission which is to facilitate the translation of basic research findings into the practice of drugabuse prevention.

project_terms:
Address;Authorship;Basic Science;Behavioral;Behavioral Research;Collaborations;Collection;Communities;Consultations;Data;Data Analyses;Data Quality;Development;Drug abuse;Educational workshop;Electronics;Ensure;Evaluation;Human Resources;Individual Differences;Instruction;Journals;Kentucky;Manuscripts;Measurement;Mentors;Methodology;Mission;Patient Self-Report;Performance;Persons;Preparation;Prevention;Principal Investigator;Psychometrics;Quality Control;Questionnaires;Research;Research Design;Research Personnel;Research Project Grants;Role;Schedule;Scientist;Service Statistics;Services;Statistical Computing;Training;Training Activity;Translational Research;Translations;Universities;Work;drug abuse prevention;graduate student;innovation;instrument;interest;meetings;neurobehavioral;outreach;psychologic;statistics;tool


application_id: 9094575
project_number: 4P50DA005312-26
project_title: Administrative Core
administering_ic: NIDA
award_notice_date: 2016-05-25
opportunity_number: PAR-10-189
application_type: 4
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2019-06-30
study_section: ZDA1-EXL-T
subproject_number: 6584
contact_pi_person_id: 8535872
contact_pi: MILICH, RICHARD
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: 2016-07-01
project_abstract:
The key functions of the Administrative Core in CDART are to: (1) provide thematic scientific integration ofthe different projects around the personality constructs under investigation; (2) create synergy across thethree proposed projects and other ongoing projects on campus; (3) facilitate interdisciplinary collaborationamong basic and prevention sciences using both neurobehavioral and psychosocial levels of analysis; and(4) oversee the long-range goal of translating our basic research into the development and implementation oftargeted prevention interventions. There are four specific aims in the Core: one scientific oneorganizational one that involves disseminating our research findings to practitioners in the field and one thatinvolves expanding leadership in the prevention science and drug abuse research communities.For the Scientific Aim the Core will provide the structure necessary to produce publications that extendbeyond the boundaries of the individual projects. The Core seeks to engender cross-cutting empiricaltheoretical and methodological articles that promote translation from basic science to prevention practice.For the Organizational Aimthe Core provides an intellectually stimulating and creative environment wherethe norm is to examine research questions and issues from a multilevel interdisciplinary perspective. Thiswill be accomplished by hosting a seminar series inviting nationally-prominent seminar speakers hosting anannual conference on issues relevant to CDART research and having an annual retreat of key personneland trainees. In terms of Dissemination of Results the Core will disseminate the research findings obtainedin the laboratory to the prevention/intervention being conducted by practitioners in the field. For theLeadership Aimthe Core will serve as a local regional national and international resource advocate andleader for the translation of basic science into efforts to prevent drug use/abuse. This will be accomplishedby building connections with other national NIDA-funded centers sponsoring workshops and trainingconferences and by having CDART faculty involved in professional organizations. The Core is alsocommitted to providing training to the next generation of drug abuse prevention researchers.RELEVANCE (See instructions):The Administrative Core is what makes the three proposed projects a Center rather than just a collection ofseparate grant proposals. The Core is the place where research questions are shared across projects ideasfor collaborative papers are generated and the actual translational research takes place.

project_terms:
Advocate;Applications Grants;Basic Science;Collection;Communities;Development;Drug abuse;Educational workshop;Environment;Faculty;Funding;Goals;Human Resources;Impulsivity;Individual;Individual Differences;Information Dissemination;Institution;Instruction;International;Investigation;Laboratories;Leadership;Mission;National Institute of Drug Abuse;Paper;Personality;Positioning Attribute;Prevention;Prevention Research;Preventive Intervention;Principal Investigator;Professional Organizations;Publications;Publishing;Research;Research Institute;Research Personnel;Resources;Science;Scientist;Series;Structure;Training;Translating;Translational Research;Translations;drug abuse prevention;drug use vulnerability;evidence base;interdisciplinary collaboration;intervention program;neurobehavioral;next generation;outreach;psychologic;psychosocial;relating to nervous system;social;substance use prevention;symposium


application_id: 9094274
project_number: 4P30CA177558-04
project_title: PROJECT 12. Protocal Review
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8636
contact_pi_person_id: 9360703
contact_pi: HAYSLIP, JOHN
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Markey Cancer Center (MCC) Protocol Review and Monitoring System (PRMS) provides thorough review of clinical trials for scientific validity feasibility and prioritization within the clinical trials portfolio and monitoring of scientific progress. The PRMS must approve all interventional cancer research prior to study initiation and has the authority to recommend closure of trials for lack of scientific progress or patient accrual. The PRMS provides a framework which aims to balance appropriate resource utilization while maximizing the opportunities for current and future patients with cancer in this region to participate in clinical trials including the underserved area of Appalachian Kentucky. The development of novel MCC investigator-initiated clinical trials and participation in high-priority national trials provide a robust portfolio of therapeutic research studies available to MCC patients.

project_terms:
Area;Basic Science;Behavioral Sciences;Cancer Center;Cancer Center Support Grant;Charge;Clinical;Clinical Data;Clinical Research;Clinical Sciences;Clinical Trials;Colorectal Cancer;Development;Documentation;England;Ensure;Equilibrium;Future;Incidence;Instruction;Kentucky;Lead;Malignant Neoplasms;Malignant neoplasm of lung;Medical center;Monitor;Patient Care;Patients;Population Heterogeneity;Population Sciences;Poverty;Process;Protocols documentation;Research Personnel;Resource Sharing;Resources;Risk Behaviors;Services;Smoking;System;Therapeutic Human Experimentation;Translations;United States;Universities;anticancer research;authority;cancer survival;data management;health disparity;novel;operation;research study;screening;translational clinical trial

public_health_relevance:
RELEVANCE (See instructions): The patients of the MCC represent a diverse population with the highest incidence rates of lung and colorectal cancers in the United States high rates of poverty and increased rates of important risk behaviors (i.e. smoking and low screening rates for some cancers). These challenges require a well-developed PRMS to facilitate effective clinical and translational trials to overcome the health disparities of this region and lead to improvement in cancer survival.


application_id: 9094273
project_number: 4P30CA177558-04
project_title: PROJECT 11. Clinical Research and Data
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8635
contact_pi_person_id: 9360703
contact_pi: HAYSLIP, JOHN
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
: The Markey Cancer Center (MCC ) Clinical l Research and Data a Management Shared Resource Facility (CRD M SRF ) coordinates and facilitates clinical cancer trials at the MCC . The major goals of the shared resource are to provide support of the clinical trial process  including implementing and regulating trials provide a centralized clinical trial l database  and integrate with the following: investigational pharmacy support  financial accounting  data safety monitoring  and quality assurance . This shared resource also assist s physician investigators in the design and subsequent conduct of clinical l trials through its support of the Investigator Initiated Trial Protocol Development Unit . It performs all regulatory reporting and quality assurance needed to comply with Good Clinical Practice in the performance of clinical trials . The CRDM SRF has Standard Operating Procedures for all its activities including training of all new faculty an d staff . From Ma y 2011 through April 2012  254 2 new patient s with cancer were seen at the MCC . Of these  145 1 were from Appalachian Kentucky . During the s time period  the CRDM SRF administrated therapeutic cancer clinical l trials that engage d 25 3 (10% ) participants in therapeutic intent clinical trials . Importantly  14 1 Appalachian patient s were engage d in therapeutic intent clinical research  a 10 % accrual rate from these disadvantaged and unique.

project_terms:
Accounting;Area;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Cancer Center;Clinical Data;Clinical Nursing Research;Clinical Research;Clinical Research Associate;Clinical Trials;Conduct Clinical Trials;Data;Databases;Development;Disadvantaged;Education;Ensure;Faculty;Financial Support;Goals;Good Clinical Practice;Industry;Kentucky;Location;Maintenance;Malignant Neoplasms;Mission;Monitor;Nurses;Participant;Patients;Performance;Pharmacy facility;Phase;Physicians;Procedures;Process;Protocols documentation;Quality Control;Reporting;Research;Research Activity;Research Infrastructure;Research Personnel;Research Priority;Resource Sharing;Resources;Risk;Safety;Services;Therapeutic;Time;Training;Translational Research;Universities;Update;anticancer research;base;cancer clinical trial;data management;design;digital;experience;protocol development;quality assurance;support tools

public_health_relevance:
The CRD M SR F provides central management an d oversight fo r coordinating  facilitating  and reporting on MCC cancer clinical trials . Th e CRDM SR F provides a central location for digital an d hard copy cancer protocols  a central database o f protocol-specific data  an update d lis t of active protocol s for investigators  an d protocol status reports . The CRDM SR F support s quality control functions  including education an d training service s for data managers and nurses and data auditing in support of the audit committee .


application_id: 9094272
project_number: 4P30CA177558-04
project_title: PROJECT 10. Cancer Reserch SRF
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8634
contact_pi_person_id: 9276771
contact_pi: DURBIN, ERIC B.
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Markey Cancer Center (MCC) Cancer Research Informatics (CRI) Shared Resource Facility facilitates collaborative research among members of the MCC through the optimal application of informatics technologies and methods that maximize the accessibility and usability of data information and knowledge for cancer research. The primary goal of CRI is to provide comprehensive and centralized data acquisition and informatics support that is readily available to cancer center members.  The Specific Aims of the CRI are to:  1. Develop and support innovative technologies for funded research studies that facilitate  accurate timely and secure data acquisition and dissemination. 2. Maintain and support a comprehensive patient-centered data warehouse offering unique  opportunities for MCC investigators to utilize integrated data sets from diverse sources ranging from genetic biomarkers to population-based surveillance data. 3. Facilitate rapid and efficient recruitment of patients to investigator-initiated trials and other  research studies. 4. Facilitate investigator access to data biospecimens and patients from Kentucky's Appalachian population. 5. Ensure the interoperability of informatics systems in compliance with evolving data standards. 6. Collaborate with the University of Kentucky (UK) Division of Biomedical Informatics to provide novel and state-of-the-art informatics solutions that increase the efficiency and accuracy of information and knowledge derived from diverse data sources.

project_terms:
Cancer Center;Cancer Center Support Grant;Clinical Research;Data;Data Set;Data Sources;Ensure;Funding;Funding Agency;Genetic Markers;Goals;Informatics;Kentucky;Knowledge;Malignant Neoplasms;Methods;Mission;NCI Center for Cancer Research;Participant;Patient Recruitments;Patients;Population;Publications;Recruitment Activity;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Secure;Services;Source;System;Technology;Universities;Work;anticancer research;biomedical informatics;data acquisition;informatics shared resource;innovative technologies;interoperability;member;novel;patient oriented;population based;research study;surveillance data;usability

public_health_relevance:
The CRI is a critical resource supporting the acquisition storage management and utilization of data information and knowledge. The CRI integrates data from population clinical and research sources to identify and recruit study participants annotate biospecimens and derive unique research datasets for MCC investigators. This shared resource provides value-added service to MCC members which has led to numerous publications and research grants from the NCI and other funding agencies.


application_id: 9094271
project_number: 4P30CA177558-04
project_title: PROJECT 9. Biostatistics SRF
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8633
contact_pi_person_id: 7719959
contact_pi: WEISS, HEIDI L
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Biostatistics Shared Resource Facility (BSRF) is a Markey Cancer Center (MCC)-managed resource providing comprehensive and centralized support that is readily accessible to cancer center investigators. The specific aims of the BSRF encompass support during study planning and study conduct and at the final stage of each project. In order to achieve these aims our services are categorized broadly into: 1) study planning power and sample size calculations for grant applications clinical trials population-based studies and preclinical experiments; 2) statistical analyses including interim and final analysis for the entire spectrum of cancer research studies; 3) statistical programming for data quality control and data processing; and 4) mentoring teaching and general consultation to MCC investigators. We also collaborate closely with MCC's Clinical Research and Data Management SRF Cancer Research Informatics SRF and other MCC shared facilities. The shared resource personnel include six faculty statisticians two master's-level statisticians and a faculty bioinformatician. Collectively they have extensive cancer-specific experience expertise and ongoing collaborations with investigators involved in studies ranging from laboratory in vitro in vivo studies in mouse models of cancer translational and bioinformatics studies in clinical samples clinical trials and population-based intervention studies. BSRF personnel are highly integrated with investigators across all research programs and interact closely with other SRFs at MCC to ensure comprehensive and seamless support. With personnel who are well-versed in all aspects of the biostatistical needs of MCC investigators the dedicated BSRF team adds significant value to the conduct of research at the MCC.

project_terms:
Address;Animals;Applications Grants;Bioinformatics;Biometry;Biostatistics Shared Resource;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Complex;Consultations;Data;Data Analyses;Data Collection;Data Quality;Databases;Development;Educational process of instructing;Ensure;Faculty;Goals;Human Resources;In Vitro;Informatics;Intervention Studies;Kentucky;Laboratories;Malignant Neoplasms;Manuscripts;Mentors;Methodology;Mission;Monitor;Phase;Play;Preparation;Quality Control;Reporting;Research;Research Design;Research Infrastructure;Research Personnel;Research Support;Resource Sharing;Resources;Role;Safety;Sample Size;Sampling;Science;Secure;Services;Staging;Toxic effect;Training;Universities;abstracting;analytical method;anticancer research;computerized data processing;data management;design;experience;in vivo;member;mouse model;neoplasm registry;population based;pre-clinical;preclinical study;programs;research study

public_health_relevance:
The Biostatistics Shared Resource Facility (BSRF) plays a key collaborative role in providing scientific and statistical input across the entire spectrum of cancer research being performed at the MCC. This SRF has demonstrated significant impact in the conduct of science at MCC as evidenced by participating as co-investigators in grant applications providing critical input in clinical trial development and trial conduct and co-authoring with investigators in all research programs of the MCC.


application_id: 9094270
project_number: 4P30CA177558-04
project_title: PROJECT 8. Biospecimen
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8632
contact_pi_person_id: 8828637
contact_pi: CIBULL, MICHAEL
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Biospecimen and Tissue Procurement Shared Resource Facility (BSTP SRF) procures and distributes biospecimens and provides expertise and support to the University of Kentucky (IJK) Markey Cancer Center (MCC) researchers to perform specialized histopathologic immunohistochemical and molecular analyses. The use of both neoplastic and non-neoplastic human and animal tissues is a key component of translational population-based and basic science cancer research. The goals of the facility are to provide formalin-fixed paraffin-embedded (FFPE) tissues frozen tissue blood and other specimens and histopathological and immunohistochemistry expertise for the studies related to the aims of Markey Cancer Center (MCC)-supported research projects. To meet these goals the following Specific Aims are proposed: 1) to provide quality-controlled human tissue biospecimens necessary for all research studies including both frozen and FFPE tissues annotated with clinical follow-up and outcomes; 2) to provide expert pathological review for all clinical specimens utilized in the projects and to provide specific histopathological technical services as necessary for analysis of all clinical and animal tissues; and 3) to coordinate and facilitate acquisition and quality control of tissue samples from the MCC affiliate hospitals required for the studies. The BSTP SRF will leverage the existing resources within the MCC the UK Department of Pathology and Laboratory Medicine the MCC Clinical Research and Data Management Shared Resource Facility and the Kentucky Cancer Registry thus assuring that this core benefits from previous efforts and techniques and that funds are used efficiently without reproducing existing facilities.

project_terms:
Appalachian Region;Basic Science;Blood;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Clinical;Clinical Data;Clinical Research;Collaborations;Colorectal Cancer;Formalin;Freezing;Funding;Goals;Hospitals;Human;Immunohistochemistry;Incidence;Individual;Kentucky;Laboratories;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Medicine;Molecular;Outcome;Paraffin Embedding;Pathology;Positioning Attribute;Process;Production;Quality Control;Research Personnel;Research Project Grants;Resource Sharing;Resources;Sampling;Services;Specimen;Structure of nail of toe;Surgical Pathology;Techniques;Tissue Microarray;Tissue Procurements;Tissue Sample;Tissues;Translational Research;Underserved Population;Universities;Urine;animal tissue;anticancer research;data management;digital imaging;follow-up;human tissue;meetings;neoplasm registry;neoplastic;novel;population based;repository;research clinical testing;research study

public_health_relevance:
A central biospecimen repository processing and analysis facility specifically for cancer provides for productive and efficient use of resources to achieve the specific aims of cancer research projects in a timely fashion. A particularly novel aspect of our facility is the large sample repository (tissue blood urine toenails) from individuals in Appalachia an underserved population with a disproportionate incidence of lung and colorectal cancer. This repository has facilitated population-based studies in this region.


application_id: 9094269
project_number: 4P30CA177558-04
project_title: PROJECT 7. Free Radical
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8631
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
There is increasing evidence that oxidative damage and free radicals with sequelae of altered cellular energetics and protein alterations are important in the initiation promotion invasion metastasis and treatment of cancers. Moreover oxidative damage and free radicals also are implicated in the side effects of normal tissue injury following cancer therapy including chemotherapy radiafion and biological modifiers. The Free Radical Biology in Cancer Shared Resource Facility (FRBC SRF) was established to provide expertise in and analyses of free radicals cellular energetics and reactive species as well as proteomics in cancer and cancer biology for Markey Cancer Center (MCC) investigators who perform basic pre-clinical and clinical research. The four basic services provided by the FRBC SRF are: 1) Analysis of markers of oxidative and nitrosative stress; 2) Molecular biological manipulation of biological systems with which to investigate redox signals including measurements of mitochondrial function by Seahorse technology; 3) Proteomics identification of differentially expressed differentially oxidized or differentially covalently modified proteins in various cancer-related systems; 4) Electron paramagnetic resonance (EPR) detection of free radicals. Development of new applications and methodology for better understanding of the roles of free radicals in cancer and cancer chemotherapy and technical assistance with grant and manuscript preparation by MCC investigators will also be provided. Included in these functions of the considerable expertise of the FRBC SRF Technical Advisory Committee to educate MCC investigators on proper sample handling and preparation methods so that reliable precise and artifact-free assay results are obtained. Multiple investigators from all four research programs of the MCC (Redox Injury and Repair [RR]; Cancer Cell Biology and Signaling [CS]; Cancer Prevention and Control [CP]; and Drug Discovery Delivery and Translational Therapeutics [DT]) have used one or more services of the FRBC SRF. Indeed even as a relatively new shared resource the FRBC SRF still had usage by 26% of MCC investigators.

project_terms:
Address;Adverse effects;Advisory Committees;Area;Bioenergetics;Biological;Biological Assay;Biological Sciences;Biology;Buffers;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Cellular biology;Chemotherapy-Oncologic Procedure;Clinical Research;Clinical Trials;Detection;Development;Electron Spin Resonance Spectroscopy;Etiology;Evaluation;Free Radicals;Freezing;Genus Hippocampus;Grant;Injury;Investigation;Ions;Kentucky;Lipids;Malignant Neoplasms;Manuscripts;Measurement;Measures;Mediating;Membrane;Metabolism;Metals;Methodology;Methods;Mitochondria;Modeling;Modification;Molecular;Morphologic artifacts;Neoplasm Metastasis;Normal tissue morphology;Nucleic Acids;Oxidation-Reduction;Oxidative Stress;Preparation;Proteins;Proteomics;Reagent;Research;Research Personnel;Resource Sharing;Resources;Role;Sampling;Services;Signal Transduction;Strategic Planning;System;Techniques;Technology;Therapeutic;Training;Universities;biological systems;cancer cell;cancer prevention;cancer therapy;carcinogenesis;cell injury;chemotherapy;differential expression;drug discovery;injury and repair;insight;instrumentation;interest;member;mitochondrial dysfunction;nitrosative stress;organizational structure;oxidative damage;pre-clinical;programs;sample fixation;tumor progression

public_health_relevance:
Damaging free radicals are produced by cancers and with various cancer treatments. When cells are damaged evidence of free radical-induced oxidative or nitrosative stress becomes apparent. The Free Radical Biology in Cancer Shared Resource Facility addresses these issues for members of the MCC by determining markers of oxidative stress measuring oxidative stress-mediated mitochondrial dysfunction using Seahorse technology and identifying aberrant cellular proteins using proteomics.


application_id: 9094268
project_number: 4P30CA177558-04
project_title: PROJECT 6. Flow Cytometry
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8630
contact_pi_person_id: 1878476
contact_pi: COHEN, DONALD A
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Markey Cancer Center (MCC) Flow Cytometry and Cell Sorting Shared Resource Facility (FCCS SRF) provides University of Kentucky (UK) cancer researchers with comprehensive state-of-the-art analytical flow cytometry and cell sorting services to support both human and animal studies. The goals of the FCCS SRF are to provide: 1) multiparameter cell phenotyping; 2) analysis of DNA content and cell cycle; 3) analysis of cellular apoptosis and necrosis; 4) quantification of cell cytotoxicity; 5) intracellular cytokine analysis; 6) measurement of cell activation parameters; 7) high speed cell sorting of live human and animal cells under biocontainment conditions; and 8) single cell cloning of sorted cells. Another important function of the shared resource is to assist researchers in data analysis of flow cytometric studies and to help investigators in the development of new flow cytometric assays or approaches as needed for their research efforts. Finally FCCS SRF addresses the future needs of investigators by adding new and updated instrumentation to the facility that will expand the number of techniques and approaches available to cancer researchers at the university.

project_terms:
Address;Animals;Apoptosis;Basic Science;Biological Assay;Cancer Center;Cancer Center Support Grant;Cancerous;Cell Cycle;Cell Separation;Cells;Characteristics;Clinical Research;Clone Cells;Data Analyses;Development;Faculty;Flow Cytometry;Funding Agency;Future;Goals;Human;Institutes;Kentucky;Life;Malignant Neoplasms;Measurement;NCI Center for Cancer Research;Necrosis;Normal Cell;Output;Phenotype;Ploidies;Publications;Research;Research Personnel;Research Project Grants;Resource Sharing;Sampling;Services;Signal Transduction;Sorting - Cell Movement;Speed;Techniques;Tissues;Training;Translational Research;United States National Institutes of Health;Universities;Update;anticancer research;cytokine;cytotoxicity;instrument;instrumentation;member;operation;programs

public_health_relevance:
Thirty-three cancer researchers from the four MCC research programs use FCCS SRF services for analysis and sorting of basic clinical or translational research samples. FCCS SRF services offer cancer investigators the ability to assay phenotypic and functional characteristics of cells from normal and cancerous tissues. Value-added service from FCCS SRF has led to numerous publications and research grants from the NCI other NIH institutes and additional funding agencies.


application_id: 9094267
project_number: 4P30CA177558-04
project_title: PROJECT 5. Program Leaders
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8629
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Program Leaders for the Markey Cancer Center (MCC) provide cohesive leadership for promoting the research activities within and among the program areas. They assure continued interchange program planning and evaluation and educational exchange within their program. The Program Leaders identify areas of need within their research program and work with leadership of the cancer center to establish priorities and pursue recruitment in their respective areas. They are involved in identifying the shared resource needs of their program members and encourage collaborations between programs by communicating with leaders of other programs on possible areas of interactions and collaborations. They inform the appropriate Associate Director and the MCC Director on program activities and serve on the MCC's Scientific Advisory Panel and the Program and Shared Resource Leaders Committee. The four research programs of the MCC) are: Program 1: Cancer Cell Biology and Signaling Program 2: Cancer Prevention and Control Program 3: Drug Discovery Delivery and Translational Therapeutics Program 4: Redox Injury and Repair

project_terms:
Area;Cancer Center;Cancer Center Support Grant;Cancer Control;Cellular biology;Collaborations;Evaluation;Kentucky;Knowledge;Leadership;NCI Center for Cancer Research;Oxidation-Reduction;Research;Research Activity;Resource Sharing;Signal Transduction;Therapeutic;Universities;Work;cancer cell;cancer prevention;cancer research center director;drug discovery;injury and repair;innovation;member;programs;research study

public_health_relevance:
The four Markey Cancer Center research programs provide an exchange of scientific knowledge with their program members and with members of the other research programs by collaborating on innovative research studies.


application_id: 9094266
project_number: 4P30CA177558-04
project_title: PROJECT 4. Admin
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8628
contact_pi_person_id: 9098327
contact_pi: GOSKY, DAVID M
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Markey Cancer Center (MCC) Administration has as its primary focus the provision of efficient and effective managerial planning and financial leadership and by doing so adding value to all MCC research programs shared resource facilities and all other services. Within that role MCC Administration provides important administrative support services to facilitate and enhance scientific productivity and collaboration among its 108 faculty research members who are organized into four research programs and who utilize MCC-supported shared resources. Administrative services include:   Coordination and participation in center-wide strategic planning and evaluation efforts.  Stimulation and support of inter- and intra-programmatic activities including grant development consultation and direct service support meeting organization and documentation and retreat/seminar/symposia coordination.  Administrative oversight and support for MCC-supported shared resources including the establishment of user fees provision of billing and auditing services coordination of and participation in oversight committees and evaluations.  Oversight of all center-related development/fundraising activities.  Fiscal management of university and Markey Cancer Foundation accounts related to the center.  Facilities management and management of all other assigned MCC space and equipment  Coordination of new faculty recruitment in collaboration with other university departments.  Human resource management of center staff.  Management of MCC membership including new application processes and annual reviews.  Administration of pilot project and other internal research award processes.  Computer networking and design of research management databases.  Coordination of internal communications and public relations for all center members.  From 2009 to the present MCC Administration has expanded staffing levels from 11.5 FTE to 19.5 FTE and in that process further developed key areas of administrative support in research communications shared resource facility development and financial management. This unit also oversaw a dramatic 40% expansion of MCC-controlled space including new construction.

project_terms:
Accountability;Accounting;Applications Grants;Area;Award;Cancer Care Facilities;Cancer Center;Cancer Center Support Grant;Clinic;Collaborations;Communication;Communication Research;Consultations;Data Base Management;Development;Documentation;Electronic Mail;Ensure;Equipment;Evaluation;Event;Expenditure;Faculty Recruitment;Fees;Floor;Foundations;Goals;Grant;Grant Review;Housing;Human Resources;Information Technology;Kentucky;Leadership;Maintenance;Malignant Neoplasms;Mission;NCI Center for Cancer Research;Newsletter;Occupational activity of managing finances;Pilot Projects;Policies;Process;Productivity;Public Relations;Reporting;Request for Applications;Research;Research Activity;Research Support;Resource Sharing;Resources;Role;Series;Services;Strategic Planning;Training;United States National Institutes of Health;Universities;Vision;base;cancer research center director;career development;computer design;computer network;cost effective;data management;equipment acquisition;experience;faculty research;meetings;member;operation;peer;programs;symposium;web site

public_health_relevance:
The Markey Cancer Center Administration is an essential component of the center's overall efforts in that it provides key services - fiscal management meeting/project/program coordination facilities management and communication - to ensure that the center is able to meet its mission vision and strategic goals.


application_id: 9094265
project_number: 4P30CA177558-04
project_title: PROJECT 3. Dev Funds
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8627
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Markey Cancer Center (MCC) will utilize developmental funds leveraged with institutional and philanthropic funds to support pilot grants and strategic new faculty recruitments. Pilot grant funding ($125000) from the CCSG will support collaborative and interdisciplinary cancer research focusing on MCC priority areas; funded projects will be carried out by interactions between MCC members in our four research programs and supported by our six shared resource facilities. Pilot funds will stimulate high return on investment research that makes a significant impact in the field of basic clinical population or translational cancer research. New faculty recruitment priorities have been established based on the MCC Strategic Plan in consultation with Senior and Program Leaders and include recruitment of: 1) a senior level molecular epidemiologist in years 1-3 ($50000 each year); and 2) a drug discovery scientist in years 4-5 ($50000 each year).

project_terms:
American Cancer Society;Area;Award;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Clinical;Collaborations;Consultations;Data;Development;Epidemiologist;Extramural Activities;Faculty;Faculty Recruitment;Fostering;Funding;Funding Agency;Generations;Goals;Grant;Interdisciplinary Study;Investments;Kentucky;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Peer Review;Philanthropic Fund;Population;Process;Publications;Recruitment Activity;Request for Applications;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Scientist;Strategic Planning;Translational Research;United States National Institutes of Health;Universities;anticancer research;base;drug discovery;member;programs;success

public_health_relevance:
Developmental funds will allow the MCC to invest in those areas of cancer research that present the greatest opportunity and are vital to the continued success of the MCC. The MCC requests Developmental Funds from the CCSG to fund pilot research projects and to recruit new faculty; both endeavors will support the goal of translational research.


application_id: 9094264
project_number: 4P30CA177558-04
project_title: PROJECT 2. Planning and Evaluation
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8626
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
Continual planning and evaluation have been key to the development and sustained excellence of the research infrastructure at the Markey Cancer Center (MCC). Planning and evaluation activities are accomplished through the internal and external advisory boards councils and committees that provide the Director and Senior Leadership ongoing guidance and support. The MCC External Advisory Board (EAB) is the primary external mechanism for review and advice on the MCC's progress in basic and translational research and community research. Internal mechanisms include the advice and support of MCC's Senior Leaders who formally comprise the MCC Director's Council; the MCC Scientific Advisory Panel; and an Internal Advisory Board (lAB) comprised of deans center directors and department chairs at the University of Kentucky. Other planning and evaluation efforts occur at the program and shared resource levels. Shortly after joining the MCC in 2009 Dr. Evers and the Senior Leadership developed a strategic plan for the MCC which has served as a road map to guide the development of scientific research programs and initiatives the reorganization of shared resources required to facilitate and achieve the scientific goals and strategic recruitments of basic and translational scientists who will synergize and further strengthen ongoing research efforts over a five-year period. The strategic plan outlines directions for research to be developed the need for expanded services within existing shared resources and organizational strategies to improve collaboration and interdisciplinary interactions. This strategic plan is regularly reviewed for progress and revised. The most recent review and revision process was conducted in 2012 to reflect the tremendous progress that has occurred over three years and to redefine the strategic goals for the next five years based on the stronger foundations that are now in place.

project_terms:
Address;Advertisements;Appalachian Region;Area;Award;Basic Science;Behavioral;Biological Markers;Cancer Burden;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Research;Clinical Trials;Collection;Colorectal Cancer;Communities;Department chair;Department of Defense;Development;Diagnosis;Enrollment;Environmental Exposure;Epigenetic Process;Evaluation;Faculty;Foundations;Future;Genetic;Goals;Growth;Health;Incidence;Interdisciplinary Study;Kentucky;Laboratories;Lead;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Maps;Marketing;Measurable;Mentors;Molecular Epidemiology;Oncologist;Organ;Outcome;Patients;Policies;Population;Prevention;Process;Publications;Regulation;Research;Research Infrastructure;Research Personnel;Resource Sharing;Rural;Scientist;Services;Site;Site Visit;Strategic Planning;TNFRSF5 gene;Therapeutic;TimeLine;Tobacco;Translational Research;Universities;Update;Validation;Wages;West Virginia;Woman;Work;assay development;base;cancer clinical trial;cancer health disparity;cancer research center director;cancer therapy;career;improved;interdisciplinary collaboration;lung carcinogenesis;malignant breast neoplasm;member;novel;population based;pre-clinical;programs;repository;research study;sarcoma;social;success;survivorship

public_health_relevance:
The MCC has set up an ongoing and continual planning and evaluation process which has been instrumental in the dramatic growth in translational and interdisciplinary research collaborative publications and interactions and enrollment in clinical trials.


application_id: 9094261
project_number: 4P30CA177558-04
project_title: PROJECT 1 Senior Leadership
administering_ic: NCI
award_notice_date: 2016-06-24
opportunity_number: PAR-11-005
application_type: 4
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8625
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Markey Cancer Center (MCC) is directed by B. Mark Evers MD with the assistance of nationally recognized leaders in cancer research prevention and clinical care. Senior Leadership of the MCC includes: Susanne M. Arnold MD (Associate Director for Clinical Translation); David M. Gosky MA MBA (Associate Director for Administration); Daret St. Clair PhD (Associate Director for Basic Research) and Thomas Tucker PhD MPH (Associate Director for Cancer Prevention and Control). This highly experienced Senior Leadership team works together to ensure consistency in the shared vision and goals of the MCC; to develop synergistic and highly collaborative interactions among the basic translational and clinical components of the Center; to plan proactive approaches to the development of the research base and resources; to effectively leverage all available resources at the University of Kentucky and at the state and national levels; to engage in community outreach and philanthropy; and to oversee all activities of the MCC.  This Senior Leadership team meets several times a month in some capacity (i.e. in the context of various MCC Board/Committee/Council meetings one-on-one with the Director and bi-weekly as a Director's Council). They provide critical advice and recommendations to the Director based on those interactions. All final authority for decisions on behalf of the MCC resides with the Director.

project_terms:
Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Control;Clinical;Community Outreach;Doctor of Philosophy;Ensure;Evaluation;Goals;Kentucky;Leadership;Prevention;Recommendation;Resources;Strategic Planning;Time;Translations;Universities;Vision;Work;anticancer research;authority;base;cancer prevention;clinical care;experience;meetings;member;research and development

public_health_relevance:
Support is requested for several members of the MCC Senior Leadership team who provide advice and recommendations to the Director regarding the strategic planning and evaluation of the Center's efforts.


application_id: 9093852
project_number: 4R01NS083405-04
project_title: Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
administering_ic: NINDS
award_notice_date: 2016-06-23
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: NS
serial_number: 083405
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-L(02)M]
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): We have previously documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and protein modification (carbonylation and tyrosine nitration) to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). The PN-mediated oxidative damage leads to brain mitochondrial dysfunction and ultimately failure. As a consequence of oxidative compromise of mitochondrial function including calcium (Ca++) buffering) posttraumatic intracellular Ca++ overload is exacerbated leading to calpain-mediated cytoskeletal degradation neurodegeneration and neurological impairment. We have preliminarily shown that treatment with the potent LP inhibitor U-83836E with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine or with the mitochondrial permeability transition inhibitor cyclosporine (CsA) can partially attenuate posttraumatic brain LP damage mitochondrial dysfunction and calpain-mediated cytoskeletal damage in a mouse TBI model. Most importantly the window for this effect is at least 12 hrs post-injury. However our preliminary results show only a partial attenuation of post-injury LP-related neural damage' even when any of these antioxidant compounds is individually administered after injury. This partial neuroprotective effect strongly points to the logic of an antioxidant neuroprotective strategy that combines either two or all three of these mechanistically complimentary antioxidant compounds to achieve a greater degree of neuroprotection. Therefore the overall goal of the proposed experiments is to explore the hypothesis that interrupting post-traumatic secondary LP oxidative damage at multiple points will produce a quantitatively greater neuroprotective effect with less variability that will have agreater chance of translational success in future TBI clinical trials. The combination approach should not only increase the maximal neuroprotective effect but may also prolong the therapeutic window for inhibition of secondary brain injury after TBI.

project_terms:
3-nitrotyrosine;4 hydroxynonenal;Aldehydes;Antioxidants;Attenuated;Brain;Brain Injuries;Buffers;Calcium;Calpain;Clinical Trials;Complex;Cyclosporine;Dose;Effectiveness;Elements;Extravasation;Failure;Free Radicals;Functional disorder;Future;Generations;Goals;Health;Human;Impairment;Injury;Intervention;Lesion;Lipid Peroxidation;Lipids;Logic;Mediating;Membrane Lipids;Mitochondria;Modeling;Molecular;Motor;Mus;Nerve Degeneration;Nervous System Trauma;Neurologic;Neurons;Patients;Permeability;Peroxonitrite;Pharmaceutical Preparations;Phase III Clinical Trials;Phenelzine;Post-Translational Protein Processing;Production;Rattus;Reactive Nitrogen Species;Reactive Oxygen Species;Recovery of Function;Regimen;Reporting;Testing;Therapeutic;Tissues;Translating;Traumatic Brain Injury;Traumatic Subarachnoid Hemorrhage;Treatment Efficacy;Treatment Protocols;Tyrosine;attenuation;base;cognitive function;controlled cortical impact;design;improved;inhibitor/antagonist;lipid peroxidation inhibitor;mitochondrial dysfunction;mortality;neuroprotection;neurotoxic;nitration;oxidative damage;protective effect;relating to nervous system;research study;respiratory;response;success;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project will examine the potentially greater benefits that might be obtained in the rat controlled cortical impact traumatic brain injury model when multiple neuroprotective compounds that target oxidative secondary injury mechanisms are administered together. Specifically we will test a combination multi-mechanistic antioxidant treatment strategy combining two or three of the following mechanistically complimentary antioxidant compounds: 1) the lipid peroxidation-inhibiting drug U-83836E 2) the commercially available compound phenelzine that scavenges the neurotoxic lipid peroxidation-derived lipid aldehyde 4- hydroxynonenal (4-HNE) and 3) the extensively demonstrated mitochondrial protective compound cyclosporine A(CsA) which reduces post-TBI mitochondrial permeability transition and free radical leakage. After determining the best neuroprotective dose optimal treatment regimen and therapeutic efficacy window of each compound pharmacologically-optimized dosing regimens of each of the compounds will be compared in a single experiment. This will be followed by the testing of the combination effectiveness of two (U-83836E + phenelzine U-83836E + CsA phenelzine + CsA) or all three (U-83836E + phenelzine + CsA).


application_id: 9093814
project_number: 5R01HD080205-03
administering_ic: NICHD
award_notice_date: 2016-06-27
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 080205
program_official: NITKIN, RALPH M
project_start_date: 2014-09-23
project_end_date: 2019-06-30
study_section: Urologic and Genitourinary Physiology and Pathology[UGPP]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
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
budget_start_date: 2016-07-01
project_abstract:
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in impairments of locomotor sensory and autonomic functions severely affecting overall health and quality of life. Recent discoveries related to activity-dependent plasticity in humans have led to a widely implemented rehabilitation intervention Locomotor Training which includes stepping using body weight support on a treadmill with manual facilitation. Evidence suggests that this particular typeof task specific training optimizes the lumbosacral spinal circuitry. We have intriguing evidence from four SCI individuals who are unable to stand or walk showing improved bladder and sexual function after undergoing Locomotor Training. These changes in urogenital function may be due to activity-dependent plasticity of lumbosacral circuitry that mediates micturition and erectile functions.  Proper bladder management post-SCI is necessary to decrease the risk of upper urinary tract disease a major source of morbidity. The life-long urologic care is required for SCIindividuals yet most efforts treat symptoms but do not improve intrinsic function. In addition paraplegics rank sexual function as the function post-injury that should be given the highest priority in order to enhance quality of life. This proposal focuses on the mechanisms involved in the reorganization of spinal cord circuits for bladder and sexual function in response to activity-dependent plasticity induced by step training after SCI with and without epidural stimulation. Stand training and/or arm crank exercise serve as controls. Of potential mechanistic importance is that neurotrophins have been implicated in modulating bladder function. It is therefore hypothesized that weight bearing task specific training for locomotion post-SCI induces plasticity of neural networks that mediate not just walking but bladder and sexual function as well and may do so for bladder function by reducing specific neurotrophins that are elevated post-SCI.  Our unique approach will utilize the expertise of each investigator to 1) To determine whether the effect of weight-bearing task-specific training for locomotion on voiding frequency and urodynamic parameters is due to an interaction between locomotor and urinary bladder circuitry after traumatic incomplete upper motor neuron SCI in humans (versus standing or general exercise); 2) To assess the effect of LT on urine (biomarkers) and bladder (biopsy tissue) NGF and BDNF levels after severe incomplete SCI; 3) To determine the effect of weight-bearing task-specific training for locomotion on erectile function and sexual satisfaction after traumatic incomplete upper motor neuron SCI in humans; and 4) To assess the effect of epidural stimulation in combination with LT on voiding frequency urodynamic parameters erectile function and bladder/urine NGF and BDNF levels after complete and motor complete/sensory incomplete upper motor neuron SCI in humans. Our innovative multi-disciplinary study may lead to the translation of a combination approach of weight bearing step training epidural stimulationand neurotrophic factor manipulation to promote functional recovery for multiple systems following SCI.

project_terms:
Affect;Animals;Ataxia;Awareness;Biological Markers;Biological Neural Networks;Biopsy;Bladder;Bladder Dysfunction;Bladder Tissue;Body Weight;Brain-Derived Neurotrophic Factor;Caring;Case Study;Catheterization;Chemicals;Clinical;Contusions;Country;Data;Disease;Ejaculation;Electric Stimulation;Esthesia;Evaluation;Exercise;Female;Fertility;Flexor;Foundations;Frequencies;Genitourinary system;Hardness;Health;Hospitalization;Human;Hyperreflexia;Impairment;Individual;Infection;Injury;International;Intervention;Interview;Knowledge;Lead;Learning;Life;Locomotion;Locomotor training;Lower Extremity;Manuals;Mediating;Morbidity - disease rate;Motor;Motor Neurons;Operative Surgical Procedures;Oral;Outcome Measure;Paralysed;Paraplegia;Patient Self-Report;Patients;Penile Erection;Pharmaceutical Preparations;Quality of life;Questionnaires;Rattus;Recovery;Recovery of Function;Rehabilitation therapy;Reporting;Research Personnel;Residual volume;Rest;Risk;Seminal fluid;Sensory;Sex Functioning;Sexual Dysfunction;Source;Sphincter;Spinal;Spinal Cord;Spinal cord injury;Stents;Step training;System;Testing;Therapeutic;Tissues;Training;Translations;United States;Urethra;Urination;Urine;Urodynamics;Urologic Diseases;Viagra;Walking;Weight-Bearing state;arm;base;improved;improved functioning;indexing;inhibitor/antagonist;innovation;life time cost;male;neurotrophic factor;novel;phosphodiesterase V;pressure;prevent;response;satisfaction;symptom treatment;treadmill;urologic

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) results in devastating effects on overall health and quality of life. The Christopher and Dana Reeve Foundation has recently estimated that 1275000 people are living with paralysis from SCI in the United States alone. This country could save an estimated $400 billion on direct and indirect lifetime costs if we can find ways to treat and prevent SCI. Bladder and sexual dysfunction affects daily life reduces quality of life and results in numerous life-long health complications. Improvements in bladder and sexual function have been reported in some people with incomplete SCI while they are undergoing a new rehabilitation intervention Locomotor Training. In addition four individuals with motor complete SCI who have received epidural stimulation in combination with Locomotor Training have also reported significant improvements in bladder and sexual function. We propose unique experimental human studies to understand whether spinal cord circuits responsible for walking are also important for bladder and sexual functions and reorganize in response to Locomotor Training and/or epidural stimulation after SCI to improve these functions and alter important chemicals in the body. The knowledge gained from our innovative multi-disciplinary study may lead to the translation of non-invasive approaches that will improve bladder and sexual function in people with SCI. Because we study humans with SCI directly what we learn will be immediately applicable to patients and provide immense improvements in quality of life.


application_id: 9093805
project_number: 4R01ES023470-04
project_title: Endocrine disruptor mediated activation of PXR causes dyslipidemia
administering_ic: NIEHS
award_notice_date: 2016-06-30
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: ES
serial_number: 023470
program_official: SCHUG, THADDEUS
project_start_date: 2013-09-26
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
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 goal of this project is to investigate a novel mechanism linking exposure to endocrine disrupting chemicals (EDCs) with dyslipidemia and cardiovascular disease. The pregnane X receptor (PXR) is a nuclear receptor activated by numerous drugs xenobiotic and dietary chemicals. Many EDCs activate PXR including organochlorine and organophosphate pesticides alkylphenols phthalates polychlorinated biphenyls bisphenol A and its analogs. However the role of PXR in mediating the pathophysiological effects of EDCs in humans and animals remains elusive. Mounting evidence implicates EDC exposure in the development of chronic human diseases but the contribution of these EDCs to the etiology of cardiovascular disease (CVD) obesity and diabetes is poorly understood. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E deficient (ApoE-/-) mice. Our central hypothesis is that EDCs which activate PXR will lead to hyperlipidemia and accelerated atherosclerosis in mice thereby increasing the risk of CVD in exposed individuals. We propose the following specific aims to test this hypothesis: 1) What are the molecular mechanisms through which intestinal PXR activation induces hyperlipidemia? 2) How does exposure to FDA-approved phthalate substitute plasticizers elevate plasma lipid levels in mice? 3) Is EDC-mediated PXR activation necessary and sufficient to increase atherosclerosis development in ApoE-/- mice? Our research will establish the role of PXR in linking exposure to EDCs with hyperlipidemia and CVD and will provide novel mechanistic links explaining how EDC exposure causes atherogenic effects. These studies are broadly translational and will provide strong evidence to inform future risk assessment for EDCs.

project_terms:
Acute;Adverse effects;Affect;Agonist;Animal Model;Animals;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;CD36 Antigens;Cardiovascular Diseases;Cause of Death;Cells;Chemical Exposure;Chemicals;Chlorinated Hydrocarbons;Cholesterol;Chronic;Citrates;Cosmetics;Development;Diabetes Mellitus;Diet;Disease;Dose;Dyslipidemias;Endocrine Disruptors;Environment;Environmental Risk Factor;Etiology;Exposure to;FDA approved;Food Packaging;Future;Gene Expression;Genetic;Genetic Transcription;Goals;Health;Homeostasis;Human;Hyperlipidemia;In Vitro;Individual;Intestines;Knowledge;Lead;Link;Lipids;Liver;Mediating;Medical Device;Modeling;Molecular;Morbidity - disease rate;Mus;Nuclear Receptors;Obesity;Organophosphates;Pesticides;Pharmaceutical Preparations;Pharmacologic Substance;Pilot Projects;Plasma;Plasticizers;Play;Polychlorinated Biphenyls;Receptor Activation;Regulation;Research;Risk Assessment;Role;Testing;Variation (Genetics);Wild Type Mouse;Xenobiotic Metabolism;Xenobiotics;absorption;analog;bisphenol A;cardiovascular disorder risk;cholesterol transporters;environmental chemical;gene environment interaction;human disease;humanized mouse;in vivo;interest;mortality;mouse model;novel;packaging material;phthalates;pregnane X receptor;receptor function;research study;sensor;tool;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of death worldwide and can be caused by genetic and environmental factors. The proposed studies will investigate the mechanisms through which exposure to certain environmental chemicals leads to hyperlipidemia and cardiovascular disease. These studies will provide important new information about underlying causes of cardiovascular disease and strong evidence to inform future risk assessment for environmental chemicals.


application_id: 9093782
project_number: 5R03DE024586-02
project_title: Modulation of innate epithelial cell responses by oral commensal bacteria
administering_ic: NIDCR
award_notice_date: 2016-05-16
opportunity_number: PAR-13-348
application_type: 5
activity_code: R03
ic: DE
serial_number: 024586
program_official: CHANDER, PREETHI
project_start_date: 2015-07-01
project_end_date: 2018-05-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 9641157
contact_pi: GONZALEZ, OCTAVIO ALBERTO
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
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 DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The mechanisms through which a persistent recognition of oral commensal bacteria by oral epithelial cells (OECs) mitigates an uncontrolled inflammatory response of the oral mucosa remain unknown. Evidence suggests that epithelial cells may discriminate between commensals and pathogenic bacteria through differential activation of responses particularly cytokine/chemokine patterns which ultimately influence both innate and adaptive arms of the immune response. Recent work in our laboratory has been identifying patterns of OECs responses following challenge with commensal and pathogenic oral bacteria. The results showed a significantly more robust (quality and quantity) chemokine transcriptional activity in response to the oral commensal S. gordonii (Sg) compared to the outcomes following challenge with the oral pathogens F. nucleatum (Fn) and P. gingivalis. Subsequent protein analysis of selected chemokines showed that there was a clear disconnect between the Sg-induced chemokine transcriptional activation and the reduced and limited protein levels found in OEC extracts and supernatants in comparison with the effect of Fn which despite inducing lower mRNA chemokines levels (2 to 4-fold less) enhanced a robust protein chemokine production as previously shown. Therefore we hypothesized that Sg and perhaps other oral commensal bacterial species have the ability to efficiently activate regulatory mechanisms for chemokine transcription and translation in order to minimize pathological inflammatory responses driven by OECs in mucosal tissues. Consistently preliminary analysis showed that Sg has the ability to significantly up-regulate (>2- fold) the expression of 115/2578 miRNAs in OECs whereby miR-663a miR-4516 miR492 and miR193a-5p have validated gene targets involved in TLR- and cytokine-induced chemokine transcription and translation. To test this hypothesis we propose the following two specific aims: (i) To determine the chemokine transcriptional and translational responses of OECs to oral commensal bacteria and (ii) To determine the role of specific miRNAs in regulating the chemokine production induced by oral commensal bacteria in OECs. To address these knowledge gaps we will use OEC cultures to: (a) determine whether the disconnect between transcription and translation of chemokines in OECs is common feature of oral commensal bacterial species and (b) determine the effect of oral commensals on the expression of specific miRNAs as regulators of these inflammatory molecules. The contribution of this investigation is expected to be the identification of the activ regulation of inflammatory responses in OECs by specific miRNAs as a potential "tolerogenic mechanism" by which oral commensal bacteria maintain symbiosis with the host. Importantly diminutions of miRNAs that would be activated specifically by oral commensal bacteria (e.g. during dysbiosis) could be related to pathologic inflammatory changes observed in disease. This project's significance will enable a better understanding of the cellular and molecular mechanisms involved in the "tipping point" between epithelial tolerogenic and pathologic responses to oral bacteria. The results are expected to contribute to a strong evidence-based foundation for future studies designed to target these mechanisms and identify new molecular target(s) associated with oral bacteria-regulated epithelial chemokine production and will ultimately provide new opportunities for the development of innovative approaches to prevent/treat periodontitis.

project_terms:
Address;Adverse effects;Affect;Bacteria;Birth;CCL20 gene;CXC Chemokines;Cell Culture Techniques;Cell Extracts;Characteristics;Development;Disease;Dose;Ecology;Environment;Epithelial;Epithelial Cells;Equilibrium;Evaluation;Foundations;Fusobacterium nucleatum;Future;Gene Targeting;Genes;Genetic Transcription;Goals;Health;Homeostasis;IL8 gene;Immune response;Inflammation;Inflammatory;Inflammatory Response;Investigation;Knowledge;Laboratories;Lead;Mediating;Messenger RNA;MicroRNAs;Molecular;Molecular Target;Mucous Membrane;Oral;Oral mucous membrane structure;Outcome;Pathologic;Pattern;Periodontal Diseases;Periodontitis;Porphyromonas gingivalis;Production;Protein Analysis;Proteins;Public Health;Regulation;Research;Research Design;Role;Streptococcus gordonii;Surface;Symbiosis;Taxon;Testing;Tissues;Transcriptional Activation;Translating;Translations;Up-Regulation;Work;arm;beta-Chemokines;chemokine;combat;commensal microbes;cytokine;design;evidence base;immunopathology;innovation;microbial;microbiota;oral bacteria;oral commensal;oral pathogen;pathogen;pathogenic bacteria;periopathogen;prevent;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will provide and evidence-based foundation for further mechanistic studies designed to identify specific miRNAs mediating the epithelial tolerogenic and pathologic responses to oral commensals which will provide new opportunities for the development of innovative approaches to prevent/treat periodontal disease and its potential adverse effects in systemic health.


application_id: 9093679
project_number: 5R01AG046920-03
project_title: Novel Actions of Metformin to Augment Resistance Training Adaptations in Older Ad
administering_ic: NIA
award_notice_date: 2016-04-27
opportunity_number: PA-12-271
application_type: 5
activity_code: R01
ic: AG
serial_number: 046920
program_official: DUTTA, CHHANDA
project_start_date: 2014-09-30
project_end_date: 2019-05-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: BAMMAN, MARCAS M;KERN, PHILIP A
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: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The loss of skeletal muscle mass and strength with advancing age reduces quality of life and is a major factor limiting an elderly person's chance of living independently. Progressive resistance exercise training (PRT) is the most effective intervention identified to increase muscular strength and combat muscle atrophy of aging; however overall the muscle response to PRT is blunted and highly variable in the elderly. Our research team has determined that the abundance of anti-inflammatory alternatively activated M2 macrophages in muscle predicts response to PRT in the elderly; those with the highest number of M2 macrophages and lowest inflammatory gene expression prior to the start of training gained the most mass. Further reexamination of muscle biopsies obtained in a study on insulin resistance showed that metformin treatment increased M2 macrophage abundance and decreased inflammatory cytokine gene expression. These provocative findings have led us to our central hypothesis that adjuvant metformin may improve the responses to PRT in the elderly by altering the muscle tissue inflammatory environment thereby enhancing mechanisms that drive PRT-induced myofiber hypertrophy. In Aim 1 we will determine if metformin treatment augments skeletal muscle size and strength gains in conjunction with PRT in older functionally limited adults. Participants will be recruited and randomized to receive either placebo or metformin for 2 weeks followed by a 14 week PRT program with continued drug/placebo treatment. Gains in muscle size and strength will be quantified. In Aim 2 we will identify cellula and molecular responses in muscle to metformin which are associated with improved response to PRT. Muscle macrophages inflammatory gene expression and anabolic and inflammatory signaling pathways will be examined in muscle biopsies. Finally mechanisms underlying metformin effects on muscle response to training using a human muscle cell culture system modeling exercise and the muscle microenvironment will be explored in Aim 3. Prospective identification of individuals likely to be refractory to routine exercise programs and determiningthe effectiveness of metformin in improving muscle growth response to PRT may contribute to the development of an affordable personalized approach to maintain or restore skeletal muscle mass and strength thereby promoting longer healthspan.

project_terms:
Adjuvant;Adult;Aging;Anti-Inflammatory Agents;Anti-inflammatory;Area;Biopsy;Blinded;Cell Culture System;Clinical Research;Coculture Techniques;Conditioned Culture Media;Cytokine Gene;Development;Disabled Persons;Effectiveness;Elderly;Environment;Exercise;Gene Expression;Goals;Growth;Health;Human;Hypertrophy;In Vitro;Individual;Inflammatory;Insulin;Insulin Resistance;Intervention;Life;Mediating;Metabolic;Metformin;Modeling;Molecular;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;Myoblasts;Nuclear;Organ;Participant;Persons;Pharmaceutical Preparations;Phenotype;Physiological;Placebo Control;Placebos;Positioning Attribute;Quality of life;Randomized;Recruitment Activity;Refractory;Regulation;Research;Resistance;Risk;Signal Pathway;Skeletal Muscle;Stretching;System;Testing;Time;Training;age related;cell type;combat;cost;effective intervention;exercise program;exercise training;frailty;glucose uptake;improved;improved functioning;in vivo;insulin sensitivity;macrophage;monocyte;muscle form;muscle hypertrophy;muscle strength;novel;personalized approach;physical inactivity;predicting response;prevent;programs;prospective;response;sarcopenia;satellite cell;skeletal;strength training;vastus lateralis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Resistance exercise training is the most effective intervention identified to combat loss of skeletal muscle mass and strength with advancing age; however the response to exercise is blunted and highly variable in the elderly. Prospective identification of individuals likely to be refractory to routine exercise programs and determining the effectiveness of metformin in improving the muscle growth response may contribute to the development of a low cost personalized approach to prevent frailty in the elderly.


application_id: 9093232
project_number: 1R21NS096670-01
project_title: Mitochondrial Transplantation Strategies to Promote Recovery after Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2016-01-26
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: NS
serial_number: 096670
program_official: JAKEMAN, LYN B
project_start_date: 2016-04-01
project_end_date: 2018-03-31
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;Contusions;Data;Dose;Endothelial Cells;Fixatives;Fostering;Frequencies;Functional disorder;Future;Goals;Hindlimb;Histological Techniques;Histology;Homeostasis;Image;Immunohistochemistry;Inflammation;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 injury;Subcellular Fractions;Techniques;Testing;Therapeutic;Time;Tissues;Transplantation;Traumatic injury;base;cell type;clinically relevant;design;dosage;gait examination;improved;inflammatory marker;injured;innovation;insight;muscle transplantation;nano;neuroprotection;novel therapeutic intervention;novel therapeutics;prevent;public health relevance;research study;response;stem;targeted treatment;tissue fixing;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: 9091809
project_number: 1R21AI124081-01
project_title: Regulation of GC B Cells by Transcription Factor STAT3
administering_ic: NIAID
award_notice_date: 2016-03-01
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 124081
program_official: JOHNSON, DAVID R
project_start_date: 2016-03-01
project_end_date: 2018-02-28
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 differentiation;B-Cell Activation;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;Inbred MRL lpr Mice;Inflammatory;Interleukin-6;Intervention;Kidney;Kinetics;Knock-out;Knockout Mice;Life;Lupus;Maintenance;Measures;Memory B-Lymphocyte;Messenger RNA;Molecular;Mus;Organ;Pathogenesis;Pathology;Pathway interactions;Patients;Phase;Phosphorylation;Plasma Cells;Play;Process;Production;Reaction;Regulation;Role;STAT protein;Serum;Signal Pathway;Signal Transduction;Small Interfering RNA;Source;Staging;Structure;Structure of germinal center of lymph node;Systemic Lupus Erythematosus;T-Cell Activation;Testing;Time;Transcript;Transcription Factor 3;Transducers;Treatment Efficacy;autoreactive B cell;cytokine;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: 9091516
project_number: 5R01DK104653-02
project_title: Hydrogen sulfide mechanism of renal hypertension
administering_ic: NIDDK
award_notice_date: 2016-07-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 104653
program_official: NIHALANI, DEEPAK
project_start_date: 2015-07-01
project_end_date: 2019-06-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 9501257
contact_pi: SEN, UTPAL
other_pis: TYAGI, SURESH C.
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): For decades hydrogen sulfide (H2S) was known only for its neurotoxicity and as an environmental hazard. Recent findings however suggest that endogenous H2S has a variety of physiological functions and a decrease in production can lead to vascular dysfunction atherosclerosis and hypertension. This discovery has stimulated further research into its development as a potential therapeutic agent in diseases attributed to diminished H2S synthesis. In chronic kidney disease low levels of plasma H2S is often associated with a concomitant increase in homocysteine (Hcy) known as hyperhomocysteinemia (HHcy). HHcy is well known to cause vascular dysfunction. The cause and effect relationship of HHcy in renal disease can therefore adversely affect the final outcome. Because Hcy is a precursor of H2S changes in the H2S metabolism can have a significant impact on HHcy-induced pathology. However the mechanism by which HHcy causes vascular dysfunction and the role of H2S in renal protection is incompletely understood. In the body Hcy is metabolized by three enzymes cystathionine -synthase (CBS) cystathionine y-lyase (CSE) and 3- mercaptopyruvate sulfurtransferase (3MST) and produce H2S. During HHcy an impairment in these enzymes leads to deficient H2S production. Our preliminary studies suggest that HHcy results in upregulation of caveolin-1 and homocysteinylation of eNOS thus decreasing NO production. The resulting imbalance in matrix metalloproteinases and their tissue inhibitors of metalloproteinases causes accumulation of extracellular matrix proteins leading to microvascular remodeling renal dysfunction and hypertension. In this proposal we hypothesize that H2S offers renal protection from HHcy-induced renal damage by inhibition of caveolin-1 and modulation of eNOS. We will test this hypothesis in vivo and in vitro. Wild type (C57BL/6J) and genetic model of HHcy (CBS+/-) mice will be supplemented without or with H2S. To determine whether HHcy effects are caveolin-1 dependent we will use caveolin-1-/- mice supplemented with high Hcy diet. To ameliorate the HHcy- induced injury single double or triple gene delivery system employing CBS CSE and 3MST enzymes will be used to enhance conversion of Hcy to H2S. In addition to confirming the preliminary findings further studies will be performed for a deeper understanding into H2S-mediated improvement in renovascular dysfunction caused by pro-fibrotic and pro-inflammatory effects of HHcy. This research is novel because it evaluates gene delivery as a therapeutic option to ameliorate HHcy-induced microvascular remodeling renal dysfunction and hypertension.

project_terms:
3-Mercaptopyruvate sulfurtransferase;Affect;Amino Acids;Angiography;Antihypertensive Agents;Antioxidants;Atherosclerosis;Blood Pressure;Blood Vessels;Blood capillaries;Cells;Chemicals;Chronic Kidney Failure;Co-Immunoprecipitations;Collagen;Connexins;Cystathionine;Cystathionine beta-Synthase;Development;Diet;Disease;Endothelial Cells;Environmental Hazards;Enzymes;Extracellular Matrix;Extracellular Matrix Proteins;Fibrosis;Functional disorder;Future;Gap Junctions;Gelatinase A;Gelatinases;Gene Delivery;Genes;Genetic Models;Glomerular Filtration Rate;Goals;Health;Homocysteine;Homocystine;Hydrogen Sulfide;Hyperhomocysteinemia;Hypertension;Impairment;In Vitro;Inflammatory;Injury;Interstitial Collagenase;Investigation;Kidney;Kidney Diseases;Knowledge;Lead;Lyase;Mass Spectrum Analysis;Matrilysin;Matrix Metalloproteinases;Measures;Mediating;Messenger RNA;Metabolism;Methods;Molecular;Mus;NOS3 gene;Nitric Oxide;Outcome;Outcomes Research;Oxidative Stress;Pathology;Perfusion;Physiological;Plasma;Process;Production;Renal Hypertension;Renal function;Renovascular Hypertension;Reporting;Research;Reverse Transcriptase Polymerase Chain Reaction;Roentgen Rays;Role;Structure;Sulfhydryl Compounds;Supplementation;Testing;Therapeutic;Therapeutic Agents;Tissue Inhibitor of Metalloproteinases;Tissues;Up-Regulation;Vascular Diseases;Vascular remodeling;Western Blotting;blood pressure regulation;capillary;caveolin 1;collagenase;connexin 37;density;gene delivery system;histological stains;in vivo;insight;kidney vascular structure;neurotoxicity;novel;prevent

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A non-protein amino acid homocysteine at elevated levels cause vascular remodeling and dysfunction. Homocysteine however in the body metabolizes and produces hydrogen sulfide. Although high levels of hydrogen sulfide are toxic low levels are protective against varieties of vascular diseases. This study proposes to mitigate high homocysteine effects on renal vascular tissues either by hydrogen sulfide supplementation or through conversion of bad homocysteine to good hydrogen sulfide by gene manipulation. The research outcome will further our knowledge for future investigations of therapeutic potential of hydrogen sulfide in high homocysteine-associated renovascular diseases.


application_id: 9090111
project_number: 5R21ES025669-02
project_title: Mitochondrial Metabolic Reprogramming and DNA Damage in Arsenic Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2016-04-21
opportunity_number: RFA-ES-14-006
application_type: 5
activity_code: R21
ic: ES
serial_number: 025669
program_official: BALSHAW, DAVID M
project_start_date: 2015-06-15
project_end_date: 2018-04-30
study_section: ZES1-LWJ-D(ME)
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
other_pis: IZUMI, TADAHIDE ;SHI, XIANGLIN
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): Although epidemiological studies have associated arsenic (As) exposures with increased risk of lung cancer the molecular mechanisms involved in lung cancer development by arsenite exposure remain poorly defined. Recent literature has implicated altered mitochondrial (mt) metabolism oxidative stress and DNA damage in environmental As carcinogenesis but the biochemical dysregulations that underlie these processes and their interactions are unknown. It is also unclear if benchside understanding of As carcinogenesis in model systems can be translated into bedside understanding of human cancer. In this R21/R33 proposal this team of investigators will address these issues by adopting an integrated `omics approach that uses stable isotope-resolved metabolomics (SIRM) to define mt and cellular metabolic networks central to proliferation redox homeostasis and oxidative DNA damage/repair response in lung cells as perturbed by As transformation and carcinogenesis. This approach will reveal pathway changes for further testing on their dysregulations (e.g. key enzymes and related regulatory proteins) at the gene mutational epigenetic and transcriptional level by querying into genomic epigenomic and transcriptomic sequencing data. The investigators will fulfill their goal with two specific aims (SA1 & 2) in the R21 phase followed by SA3 & 4 in the R33 phase and SA1 to determine if and how mt and cellular metabolic networks are altered in As-transformed lung cells using SIRM. Transformed lung cells will be studied in vitro and in mouse xenografts using SIRM. The reprogrammed metabolic networks obtained will be related to those separately acquired in vivo from human lung cancer patients. SA2) to link ROS production mt and nuclear DNA damages/repair processes to metabolic reprogramming in As-transformed lung cells. Correlations of SA1&2 data will enable hypothesis generation for further testing of cause-and-effect relationships in SA3&4. SA3) to reveal cause-and-effect relations among altered Mt/cellular metabolic networks ROS production and DNA damage during As-induced transformation by their time-dependence. SA4) to map corresponding genetic epigenetic and gene expression changes in As-transformed lung cells for hypothesis testing on As action. Next-generation sequence data will be acquired and queried for mutational signatures epigenetic status and mRNA expression of key genes involved in the reprogrammed metabolic networks redox balance and DNA repair. These data will help delineate how As-induced genetic or epigenetic lesions lead to metabolic reprogramming or vice versa. Such integration of genomic epigenomic transcriptomic and metabolomics analysis of As action in model lung cell systems should provide unprecedentedly detailed insights into metabolic dysregulation and DNA damage in the mitochondria and how they may be linked to nuclear DNA damage and altered gene expression. The integrated `omics information will facilitate full-scale validation studies on the molecular mechanism for As-inducedcarcinogenesis and translation of such basic insights into human lung cancer resulting from As exposure (e.g. discovery of mechanistic and robust biomarker patterns).

project_terms:
Acetylcysteine;Address;Adopted;Arsenic;Arsenites;Biochemical;Biochemical Pathway;Biological Assay;Biological Markers;Biological Models;Cancer Patient;Cells;Citric Acid Cycle;Complex;Coupled;DNA;DNA Damage;DNA Repair;Data;Data Correlations;Dependence;Development;Electron Transport;Environmental Carcinogens;Enzymes;Epidemiologic Studies;Epigenetic Process;Epithelial Cells;Equilibrium;Etiology;Event;Fumarate Hydratase;Future;Gene Expression;Gene Mutation;Generations;Genes;Genetic;Genomic DNA;Genomics;Genus Hippocampus;Glucose;Glutamine;Goals;Health;Homeostasis;Human;In Vitro;Kidney;Knowledge;Lead;Lesion;Link;Literature;Lung;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mammalian Cell;Maps;Measures;Mediating;Metabolic;Mitochondria;Mitochondrial DNA;Modeling;Molecular;Mus;Mutation;Nuclear;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Pattern;Phase;Poly(ADP-ribose) Polymerases;Populations at Risk;Preventive;Process;Production;Protocols documentation;RNA;Research Personnel;Respiration;Risk;Role;Succinate Dehydrogenase;System;Testing;Therapeutic;Time;Tracer;Translating;Translations;Xenograft procedure;arsenic-induced carcinogenesis;base;carcinogenesis;cell transformation;environmental carcinogenesis;enzyme activity;epigenomics;genetic regulatory protein;in vivo;insight;mRNA Expression;metabolomics;mitochondrial dysfunction;mitochondrial metabolism;next generation;next generation sequencing;oxidative DNA damage;repaired;respiratory;response;stable isotope;transcriptome sequencing;transcriptomics;tumor;validation studies

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Environmental carcinogenesis is an important and yet difficult issue to resolve in human health in the US and worldwide due to its extreme complexity. This proposal will take advantage of the latest advances in metabolomics genomics epigenomics and transcriptomics and applies them in an integrated fashion to decipher the molecular etiology of As-induced carcinogenesis. The molecular insights to be acquired will help resolve long-standing gaps of mechanistic knowledge in As action while facilitating the discovery of robust biomarkers as well as preventive and therapeutic measures for at risk populations.


application_id: 9090059
project_number: 5R21CA198249-02
project_title: A Novel Vaccination Stratagem for Lung Cancer
administering_ic: NCI
award_notice_date: 2016-07-01
opportunity_number: PAR-13-146
application_type: 5
activity_code: R21
ic: CA
serial_number: 198249
program_official: YOVANDICH, JASON L
project_start_date: 2015-07-01
project_end_date: 2018-06-30
study_section: ZCA1-RTRB-Z(M1)
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
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): Lung cancer is a prevalent disease and consumes many lives every year. Disease relapse invasion and metastases are the main causes of death. Recent discoveries provide compelling evidence that at least some types of cancer are initiated and maintained by a small population of malignant cells called cancer-initiating stem cells (CICs). Relapse invasion and metastases are explained by the fact that CICs have a different biology than all the other tumor cells and importantly are resistant to chemotherapies and radiation. Lung CICs have been shown to represent about 1-15% of all tumor cells and can form tumors with injections as low as 100 cells. Evidence from published studies have demonstrated that human as well as rodent cancers contain populations of cells that express embryonic stem (ES) cell antigens. Cells containing these proteins also express markers used to identify lung CICs; therefore we hypothesized that ES cells and CICs share several common molecular traits. To test this hypothesis we vaccinated mice with irradiated allogeneic murine ES cells in combination with a source of granulocyte-macrophage colony stimulating factor (GM-CSF) as an immunostimulatory adjuvant (ES cell vaccine) and investigated whether an anti-tumor immune response was elicited. We discovered that ES cell vaccination is very effective in preventing both implantable and carcinogen-induced lung adenocarcinoma development without any detectable toxicity or signs of autoimmunity. Preliminary studies from our laboratory reveal that splenocytes from ES cell-immunized mice are preferentially cytotoxic to lung CICs. Experiments proposed in this application seek to expand these novel findings to convincingly demonstrate that ES cells immunize against lung cancer- associated CICs and that anti-CIC immunity is responsible for preventing lung adenocarcinoma development. A major goal of this study is to assess the potential of CIC-targeting ES cell vaccine as a treatment option for lung cancer patients. We will test the translational potential of our approach using a novel ES cell-derived exosome- based vaccination strategy (Es-exo vaccine). Experiments proposed in this study will address the in vivo efficacy of ES-exo vaccine as a cell-free vaccine modality in both prophylactic and therapeutic settings against lung cancer. The biological features responsible for the anti-tumor activities of ES-exo vaccine as well as their immunostimulatory properties will be investigated in in vitro and in vivo lung cancer mouse models. To fulfill the stated objectivesthe following aims are proposed: 1) Investigate whether lung cancer-initiating cells are targets ofES cell vaccination- induced anti-tumor immunity. 2) Evaluate the translational potential of ES cell-derived exosomes (ES-exo) as a novel cell-free vaccine for lung cancer. Our proposed study will provide important insights towards developing a safe immunotherapeutic vaccine for lung cancer onset and/or recurrence.

project_terms:
Address;Adjuvant;Age-Months;Allogenic;Animal Model;Antigens;Autoimmunity;Binding;Biological;Biology;CD8B1 gene;Cancer Biology;Cancer Patient;Carcinogens;Cause of Death;Cell-Free System;Cells;Cessation of life;Clinical Trials;Data;Dendritic Cells;Development;Disease;Disease remission;Embryo;Epithelial;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Health;Health Care Costs;Hematopoietic;Human;Immune;Immune response;Immunity;Immunization;Immunotherapeutic agent;In Vitro;Injection of therapeutic agent;Laboratories;Lead;Lewis Lung Carcinoma;Life;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Membrane;Messenger RNA;MicroRNAs;Modality;Molecular;Mus;Mutation;Neoplasm Metastasis;Patients;Platelet Factor 4;Population;Pre-Clinical Model;Property;Proteins;Publishing;Radiation;Recurrence;Recurrent disease;Relapse;Reporting;Research Design;Resistance;Risk;Rodent;Signal Transduction;Solid;Source;Splenocyte;Stem cells;T cell response;Teratoma;Testing;Therapeutic;Toxic effect;Transgenic Organisms;Translations;Treatment Efficacy;Tumor Antigens;Tumor Immunity;Undifferentiated;Vaccinated;Vaccination;Vaccines;Validation;Vesicle;Work;antitumor effect;base;cancer cell;cancer therapy;cancer type;cell type;chemotherapy;conventional therapy;cytotoxic;embryonic stem cell;exosome;in vitro Assay;in vivo;insight;intercellular communication;lung tumorigenesis;mouse model;nanoscale;neoplastic cell;novel;prevent;prophylactic;relapse risk;research study;self-renewal;stem;trait;tumor;tumorigenesis;vaccination strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A Novel Vaccination Stratagem for Lung Cancer Lung cancer patients remain at elevated risk for relapse following conventional treatment. Recent studies of lung cancer biology provide compelling evidence that lung cancer is initiated and maintained by a small population of malignant cells called cancer-initiating cells (CICs). Currently available cancer treatments may be ineffective against lung CICs. Our preliminary work using a vaccine consisting of mouse embryonic stem (ES) cells has provided validation that vaccination prevents lung cancers in mice. We propose to investigate whether ES cell vaccination as well as a novel cell-free version of the ES cell vaccine is effective in depleting lung CICs and prevent cancer. Such a vaccine will reduce health care costs and loss of life from a disease that is now a major health problem worldwide.


application_id: 9089979
project_number: 4R01DA033866-05
project_title: Brief intervention for drug-using rural women at high-risk for HIV/HCV
administering_ic: NIDA
award_notice_date: 2016-06-22
opportunity_number: PA-10-129
application_type: 4
activity_code: R01
ic: DA
serial_number: 033866
program_official: MULFORD, CARRIE FRIED
project_start_date: 2012-07-15
project_end_date: 2020-06-30
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
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 SOCIAL WELFARE/WORK
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall aim of this study is to reduce risk behaviors and increase health and behavioral health service utilization among disadvantaged drug-using rural women at high-risk for HIV and HCV. This project has potential to make a significant contribution to science by advancing knowledge about the health disparities high-risk behaviors (injection drug use sex risk) and service utilization of this high-risk vulnerable an understudied group of women during a time of emerging and significant public health risk in an Appalachian rural setting. This project will incorporate standardized screening (NIDA-modified ASSIST) to identify high-risk rural women drug users from jails including injectors. Consenting women (N=350) will be asked to participate in a baseline interview and will then be randomly assigned to one of two study groups: (1) HIV Education (HIV- Ed n=175) which includes the NIDA standard pre and post-test counseling HIV and HCV rapid testing and an information packet on existing community drug abuse and HIV/HCV resources; or (2) Motivational Interviewing- based HIV Risk Reduction (MI-HIV n=175) which in addition to what is received in the HIV-Ed group also includes an evidence-based brief intervention for high-risk women focused on an individualized plan for enhancing motivation to reduce risk behaviors and to use health and behavioral health services in the community. Specific aims include: (1) to compare the effectiveness of an evidence-based HIV risk reduction intervention (MI-HIV) to HIV Education (NIDA Standard) in reducing sex risk behaviors injection practices and drug use among a culturally unique sample of disadvantaged drug-using rural women at high-risk for HIV and HCV; and (2) to examine MI-HIV Intervention engagement as a predictor of community health and behavioral health service utilization (including drug treatment and mental health) at follow-up among disadvantaged drug- using rural women at high risk for HIV and HCV. This project is innovative because it 1) targets a high-risk and understudied group of women 2) uses brief intervention to not only reduce risk behavior but also to enhance motivation for using community health and behavioral health resources and 3) utilizes a real-world setting to identify high-risk women drug users. The long-term goal of this study is to increase access to health and behavioral health services in order to improve the quality of health of high-risk rural women.

project_terms:
AIDS/HIV problem;Address;Appalachian Region;Area;Centers for Disease Control and Prevention (U.S.);Communities;Community Health;Community Services;Consent;Counseling;Country;Criminal Justice;Disadvantaged;Drug abuse;Drug usage;Drug user;Education;Educational Intervention;Evidence based intervention;Goals;HIV;HIV risk;HIV/HCV;Health;Health Resources;Health Services;Healthcare;High Risk Woman;Injection of therapeutic agent;Intervention;Interview;Jail;Kentucky;Knowledge;Mental Health;Motivation;National Institute of Drug Abuse;Opiates;Participant;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Pre-Post Tests;Prevalence;Public Health;Random Allocation;Randomized;Reporting;Research;Research Personnel;Resources;Risk;Risk Behaviors;Risk Reduction;Rural;Sampling;Science;Services;Staging;Testing;Time;United States National Institutes of Health;Vulnerable Populations;Walkers;Woman;Women's Group;base;behavioral health;brief intervention;compare effectiveness;comparison group;cost;design;evidence base;follow-up;health disparity;health service use;high risk;high risk behavior;improved;injection drug use;innovation;motivational enhancement therapy;outreach;prescription opiate;response;rural area;screening;service utilization;sex risk;treatment planning

public_health_relevance:
The overall aim of this study is to reduce risk behaviors and increase health and behavioral health service utilization among disadvantaged drug-using rural women at high risk for HIV and HCV. This project has potential to make a significant contribution to science by providing knowledge about the health risk behaviors and service utilization of a vulnerable and understudied group of women during a time of emerging and significant public health risk in a rural Appalachian setting. Successful completion of the aims ofthis project will advance the delivery of a low-cost potentially high impact intervention with implications for a number of other real world settings (such as criminal justice venues) where other disadvantaged high-risk drug users can be identified and targeted for intervention.


application_id: 9089964
project_number: 4U01DA013519-14
project_title: Development of Novel Therapies or Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2016-06-22
opportunity_number: PA-10-067
application_type: 4
activity_code: U01
ic: DA
serial_number: 013519
program_official: KLINE, RICHARD
project_start_date: 2000-08-15
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-C(56)S]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
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:
DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse continues to escalate and effective treatments are not currently available. METH interacts with the vesicular monoamine transporter-2 (VMAT2) promoting both dopamine (DA) release into the cytosol and reversal of the DA transporter to increase extracellular DA concentrations which is thought to be associated with its abuse liability. The overall objective of this project is to provide a clinical candidate for the treatment of METH abuse. Recently we identified a novel small molecule (GZ-793A) which potently and selectively inhibits DA uptake by VMAT2 inhibits METH-evoked DA release from synaptic striatal vesicles and slices and exhibits selectivity does not interact with nicotinic receptors or DA transporters. Off-target evaluation at a cadre of neurotransmitter-related steroid and ion channel sites second messenger prostaglandin growth factor and hormones brain/gut peptides and enzymes revealed outstanding selectivity. Translation to whole animals models revealed that GZ-793A specifically decreases METH self-administration without altering responding for sucrose does not produce tolerance to the decrease in METH self- administration upon repeated administration and decreases METH seeking in the cue-induced reinstatement. Acute GZ793A pretreatment also protects against the neurotoxic effects of METH as measured by striatal DA depletion. Although the physicochemical properties of GZ-793A are favorable in terms of druggability GZ-793A has only 2-3% oral bioavailability likely due to the presence of the hydroxyl functionalities in the molecule which are likely sites for high first-pass metabolism. Thus new optimized analogs of GZ-793A are the focus of the current application with the goal of identifying analogs with the required pharmacological properties druggability increased oral bioavailability and acceptable pharmacokinetic profile. Compounds with these characteristics would be high value preclinical candidates for advancement toward clinical trials as treatments for METH abuse. Thus we propose to expand our existing molecular library of analogs by performing the final steps of optimization of GZ-793A to identify a high value preclinical candidate as a potential therapeutics for METH abuse. In future work the best candidate will undergo comprehensive toxicological evaluation for subsequent preparation of an Investigational New Drug application to the FDA as a proposed treatment for methamphetamine abuse.

project_terms:
Acute;Affinity;Animal Model;Behavioral;Binding Sites;Bioavailable;Biological Availability;Brain;CYP2C19 gene;CYP2D6 gene;Characteristics;Chemical Structure;Clinical;Clinical Trials;Collaborations;Corpus striatum structure;Cues;Cytosol;Data;Development;Dopamine;Dose;Drug Kinetics;Enzymes;Evaluation;Event;Exhibits;Food;Future;Generations;Goals;Growth;Half-Life;Health;Hepatic;Hormones;Hydroxyl Radical;Ilex vomitoria;In Vitro;Intravenous;Investigational New Drug Application;Ion Channel;Lead;Libraries;Lobeline;Measures;Metabolism;Methamphetamine;Modification;Molecular Bank;National Institute of Drug Abuse;Neurotransmitters;Nicotinic Receptors;Oral;Oral Administration;Outcome;Peptides;Pharmaceutical Preparations;Phase;Plasma;Preparation;Prodrugs;Property;Prostaglandins;Rattus;Rewards;Route;Safety;Salts;Second Messenger Systems;Self Administration;Site;Slice;Specificity;Steroids;Structure-Activity Relationship;Sucrose;Synapses;Synaptic Vesicles;Therapeutic;Therapeutic Agents;Translations;Variant;Vesicle;Work;analog;base;dihydrotetrabenazine;dopamine system;dopamine transporter;effective therapy;extracellular;improved;inhibitor/antagonist;methamphetamine abuse;methamphetamine effect;neurotoxic;neurotoxicity;new therapeutic target;novel;novel therapeutics;piperidine;pre-clinical;preference;second messenger;small molecule;sulfation;uptake;vesicular monoamine transporter 2;water solubility

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Currently there is no pharmacotherapeutic available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. Recently we identified a novel small molecule (GZ-793A) which potently and selectively interacts with the vesicular monoamine transporter-2 and which exhibits potency and specificity in decreasing responding for intravenous methamphetamine in an animal model of self-administration. We propose to expand our existing molecular library by performing the final steps of optimization of the chemical structure of GZ-793A with the aim of providing additional leads that are druggable orally-bioavailable high value preclinical candidates. The outcome of the proposed project is to bring the best candidate to comprehensive toxicological evaluation for preparation of an Investigational New Drug application to the FDA as a proposed treatment for methamphetamine abuse.


application_id: 9089499
project_number: 1R01CA205400-01
project_title: Distinct Redox Mechanism in Normal and Cancer Cells as a Novel Therapeutic Target
administering_ic: NCI
award_notice_date: 2016-03-24
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: CA
serial_number: 205400
program_official: BERNHARD, ERIC J
project_start_date: 2016-04-01
project_end_date: 2021-03-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ST CLAIR, WILLIAM H
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:
Acute;Address;Adverse effects;Affinity Chromatography;Amino Acids;Apoptosis;Autophagocytosis;Autopsy;Betamethasone;Biochemical;Biological Markers;Cancer Survivor;Cell Culture Techniques;Cell Line;Cells;Cessation of life;Clinical;Clinical Treatment;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Coupled;Couples;Cultured Cells;Cytotoxic Chemotherapy;Data;Development;Disulfides;Dose;Drug Compounding;Electron Spin Resonance Spectroscopy;Epithelial Cells;Evaluation;Exhibits;Experimental Animal Model;FDA approved;Family;Gene-Modified;Goals;Histology;Homeostasis;In Vitro;Inflammatory;Injury;Ionizing radiation;Knowledge;Lactones;Lead;Libraries;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Messenger RNA;Methods;Modeling;Molecular;Molecular Biology;Morbidity - disease rate;Mus;Necrosis;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Outcome;Oxidation-Reduction;Oxidative Stress;PC3 cell line;Pathway interactions;Patients;Phase I Clinical Trials;Primary Neoplasm;Prodrugs;Property;Prostate;Prostate carcinoma;Proteins;Proteomics;Quality of life;Radiation;Radiation Tolerance;Radiation therapy;Radiation-Sensitizing Agents;Radiodermatitis;Reactive Oxygen Species;Recurrence;Regimen;Research Project Grants;Role;Sesquiterpenes;Small Interfering RNA;Stable Isotope Labeling;Steroids;Sulfhydryl Compounds;Testing;Therapeutic;Tissues;Translations;Treatment Efficacy;Tumor Tissue;United States;Water;Work;base;cancer cell;cancer diagnosis;clinical practice;cytotoxic;expectation;gene product;hormone refractory prostate cancer;hormone therapy;improved;in vivo;in vivo imaging;luminescence;male;member;men;morphometry;neoplastic cell;new therapeutic target;novel;novel therapeutics;overexpression;parthenolide;personalized therapeutic;pre-clinical;prostate cancer cell;public health relevance;radiation resistance;radiation response;radiation-induced injury;radiosensitizing;response;treatment response;tumor


application_id: 9089062
project_number: 1R21EB022185-01
project_title: Vascularized cell-based device for restoring physiological homeostasis
administering_ic: NIBIB
award_notice_date: 2016-04-12
opportunity_number: PA-12-284
application_type: 1
activity_code: R21
ic: EB
serial_number: 022185
program_official: RAMPULLA, DAVID
project_start_date: 2016-04-15
project_end_date: 2018-01-31
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 8307477
contact_pi: BOYD, NOLAN LEE
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): Cell source and vascularization are two challenges to successful cell-based therapy. In this proposal we present an enabling technology for the vascularization of physiologically restored parenchymal cells derived from genetically deficient induced pluripotent stem cells (iPSC). As a proof-of-principle we have restored the low-density lipoprotein receptor (LDLR) feedback endocytosis in Familial Hypercholesterolemia (FH) iPSC. We will derive restored hepatocyte-like cells (HLC) and combine them with a unique stromal and vascularization cell source isolated from adipose tissue known as the stromal vascular fraction (SVF). The objective of this proposal is to determine the capacity of an ectopic cell-based apheresis and metabolism device to modulate circulating LDL cholesterol (LDL-C) under hypercholesterolemic conditions. We will pursue this objective through the following Specific Aims: Aim 1: Determine the apheresis device LDL-C metabolism function. In this Aim we will investigate our device design for LDL-C internalization and metabolism parenchymal cell survival device vascularization and residual pluripotent cell elimination. Aim 2: Determine the apheresis device capacity to modulate circulating LDL-C. In this Aim we will investigate the capacity of the device to engraft modulate LDL-C levels and produce human circulating proteins.

project_terms:
Address;Adipocytes;Adipose tissue;Affect;Anastomosis - action;Apolipoprotein A-I;Apolipoprotein E;Autologous;Bile Acid Biosynthesis Pathway;Bile Acids;Blood Circulation;Blood Coagulation Factor;Blood Component Removal;Blood Vessels;Cell Fraction;Cell Survival;Cell Therapy;Cells;Cholesterol Homeostasis;Complex;Data;Development;Device Designs;Device Removal;Devices;Diet;Digestion;Drug Implants;Endocytosis;Endothelium;Engraftment;Excision;Familial Hypercholesterolemia;Feedback;Functional disorder;Genetic;Genomic DNA;Hepatocyte;Homeostasis;Human;Immune;Implant;LDL Cholesterol Lipoproteins;Lipids;Liver;Location;Low Density Lipoprotein Receptor;Low-Density Lipoproteins;Mediating;Mesenchymal;Metabolism;Microcirculation;Modeling;Modification;Organ;Organoids;Pathology;Patients;Pericytes;Physiological;Plasma;Plasmids;Population;Production;Proteins;Publishing;Rag1 Mouse;Residual state;Retrieval;Source;Stream;System;Technology;Teratoma;Therapeutic;Tissue Engineering;Toxin;Triglycerides;Vascularization;base;cancer cell;cardiovascular disorder risk;chylomicron remnant;collagenase;gene product;implantation;in vivo;induced pluripotent stem cell;macromolecule;mouse model;public health relevance;receptor;receptor expression;receptor mediated endocytosis;restoration;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cell-based technologies could be used for removing circulating toxins or providing missing biomolecules due to genetic deficiencies. Induced pluripotent stem cells (iPSC) could provide an unparalleled autologous cell source for therapeutic applications; however they may require modification to restore physiological function. Additionally engineered tissues are challenged by poor vascularization. In this project we propose to develop a vascularized cell-based enabling technology that is functionally modifiable to the patient's requirements. As a proof-of-principle we will deliver hepatocyte-like cells (HLC) derived from low-density lipoprotein receptor (LDLR) deficient Familial Hypercholesterolemia iPSC that have receptor mediated endocytosis feedback control restored. The FH-HLC-LDLR will be combined with a unique vascularization cell source isolated from adipose tissue. The implant will function as an ectopic device for removal and metabolism of excess circulating LDL to reduce the risk of cardiovascular disease development.


application_id: 9088451
project_number: 5R21DC014857-02
project_title: Taste neuron connectivity and branching revealed by sparse cell genetic labeling
administering_ic: NIDCD
award_notice_date: 2016-05-25
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: DC
serial_number: 014857
program_official: SULLIVAN, SUSAN L
project_start_date: 2015-07-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-IFCN-B(03)M]
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_abstract:
DESCRIPTION (provided by applicant: A general feature of sensory organization is that neurons can be divided into different types based on molecular morphological and functional characteristics. Whether this type of organization exists in the taste system is unclear. It is generally accepted that taste receptor cells exist as different types. The next critical step is todetermine how these different taste receptor cell types can connect with the ganglion neurons that carry taste information to the brain. Because peripheral gustatory axons invade the tongue in fascicles with individual axons intertwining at every level past attempts at reconstructing single fibers have not been successful. This project will overcome this critical barrier by combining genetically-directed sparse labeling of nerve fibers with three-dimensional visualization and reconstruction in taste buds. Using these approaches we will test the hypothesis that gustatory neurons can be divided into subtypes based on their morphology (i.e. branching) and connectivity with specific types of taste receptor cells. These experiments will reveal how connections between taste cells and nerve fibers are organized. The approaches established in this project can be used in future studies to understand 1) if morphological subtypes correspond to specific molecular and/or functional subtypes 2) the branching of individual taste neurons in the central nervous system (CNS) 3) how branching patterns are established during development and 4) whether normal branching patterns are reestablished following injury disease or chemotherapy.

project_terms:
Address;Alkaline Phosphatase;Axon;Brain;Cells;Characteristics;Code;Data;Development;Dimensions;Disease;Dose;Embryonic Development;Esthesia;Fascicle;Fiber;Future;Ganglia;Genes;Genetic;Genetic Recombination;Hand;Health;Imagery;Immunohistochemistry;Individual;Injury;Invaded;Label;LoxP-flanked allele;Methods;Molecular;Morphology;Mus;Nerve Fibers;Neuraxis;Neurons;Pathway interactions;Pattern;Peripheral;Persons;Phenotype;Property;Quality of life;Receptor Cell;Research;Sensory;Signal Transduction;Specificity;Staining method;Stains;Stimulus;Sucrose;Tamoxifen;Taste Buds;Taste Disorders;Taste Perception;Testing;Time;Tongue;base;cell type;chemotherapy;ganglion cell;reconstruction;research study;response;sensory system;taste stimuli;taste system;tongue root;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Taste disorders can have detrimental effects on a person's health and quality of life. The underlying mechanisms are not understood but could result from disruption of the gustatory neurons that carry taste information to the brain. Taste ganglion neurons are largely unstudied due to a lack of appropriate tools; this project overcomes this critical barrier by developing new tools that can be used to examine taste ganglion neuron branching and peripheral connectivity following injury and in disease states.


application_id: 9088432
project_number: 4K02DA035116-04
project_title: Social Networks and HIV Risk Behaviors of Special Populations of Drug Users
administering_ic: NIDA
award_notice_date: 2016-05-20
opportunity_number: PA-11-191
application_type: 4
activity_code: K02
ic: DA
serial_number: 035116
program_official: HARTSOCK, PETER
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
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): The primary goal of this resubmitted K02 application is to further develop Dr. Carrie Oser's productive independent research career and to augment her research focus on HIV substance abuse treatment crime and health disparities by gaining new training on social networks and HIV intervention development. The K02 builds upon her focus on special populations including both rural drug users and African American drug users. The proposed training goals will provide new instruction in social networks HIV intervention development and the responsible conduct of research. The specific aims are: (1) to identify HIV and HCV risk and longitudinal changes in risk in the social networks of 503 rural out-of-treatment drug using women as compared to men; and (2) to examine the effect of social networks including structure (e.g. size density) function (e.g. emotional and instrument support) and content (e.g. attitudes towards physicians) on HIV and HCV risk behaviors and health services utilization among African American drug using women as compared to men across criminal justice status. This significant and innovative study will have strong public healt impacts and will support NIDA's Health Disparities Initiative because of its potential to contribut to our understanding of the cultural and social network correlates of health disparities among both rural and African American drug users. In addition this study improves upon the methodological limitations of previous research findings by examining various social networks (e.g. egocentric dyadic and sociocentric) and using longitudinal data in multilevel models. Thisproposed project will allow for a practical application of the substantive knowledge and analytical skills acquired from the K02 training activities and will ultimately culminate in the development of forthcoming investigator initiated NIDA grant applications. Specifically these findings will be used as a foundation for future HIV social networks based intervention to increase special populations' use of preventative health care and subsequently reduce the need for expensive medical services as well as to decrease HIV risk behaviors including drug use unprotected sex and recidivism.

project_terms:
Accounting;African American;Applications Grants;Attitude;Biological Assay;Centers for Disease Control and Prevention (U.S.);Communities;Crime;Criminal Justice;Data;Data Collection;Development;Drug Prescriptions;Drug abuse;Drug usage;Drug user;Emotional;Female;Foundations;Future;Gender;Goals;Grant;HIV;HIV Infections;HIV diagnosis;HIV risk;HIV/HCV;Health;Health Services;Hepatitis C virus;Imprisonment;Independent Scientist Award;Individual;Instruction;Intervention;Kentucky;Knowledge;Life;Link;Measures;Medical;Methodology;National Institute of Drug Abuse;Network-based;Oxycodone;Pathway Analysis;Patient Self-Report;Pharmaceutical Preparations;Physicians;Population;Prevalence;Preventive healthcare;Prisons;Public Health;Race;Research;Research Personnel;Risk;Risk Behaviors;Rural;S-nitro-N-acetylpenicillamine;Services;Social Network;Spirituality;Strategic Planning;Structure;System;Training;Training Activity;United States National Institutes of Health;Unsafe Sex;Woman;career;density;disorder prevention;experience;falls;health disparity;health service use;high risk;high risk sexual behavior;improved;injection drug use;innovation;instrument;male;men;multilevel analysis;named group;practical application;probation;recidivism;responsible research conduct;rural area;skills;social;substance abuse treatment;support network;therapy development;urban area;willingness

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This study is significant to the public health field because of its potential to understand the individual cultural and social network factors associated with HI and HCV risk behaviors among two special populations - rural drug users and African American drug users. These findings will be used as a foundation for developing social network based HIV interventions to increase special populations' use of preventative health care and subsequently reduce the need for expensive medical services as well as to decrease HIV risk behaviors including drug use unprotected sex and recidivism.


application_id: 9088298
project_number: 4R01AI095307-05
project_title: Alternative macrophage activation in acute Pseudomonas pneumonia
administering_ic: NIAID
award_notice_date: 2016-06-13
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: AI
serial_number: 095307
program_official: DAVIDSON, WENDY F
project_start_date: 2012-07-01
project_end_date: 2019-06-30
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 8968639
contact_pi: FEOLA, DAVID
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:
DESCRIPTION (provided by applicant): Alternative macrophage activation regulates inflammatory responses to pathogenic organisms. Most work to date has characterized their role in Th2-type immune responses. Alternatively activated macrophages (AAM) have been shown to inhibit classically activated macrophage proliferation and function as well as to suppress T cell mediated immune responses through the production of the type II cytokine transforming growth factor (TGF)- and arginase-1. While primarily functioning to orchestrate remodeling and repair mechanisms arginase-1 and TGF are also important in controlling lung homeostasis and suppressing inflammation. The function of AAM in regulating the inflammatory response to extracellular Gram-negative bacterial infection in the lungs has not been characterized. Understanding the role of AAM in this setting is critical for advancing our understanding of immune mechanisms affecting patients with cystic fibrosis (CF) and other chronic pulmonary inflammatory conditions. CF causes progressive life-threatening lung damage due in large part to repeated dysregulated inflammatory responses to Pseudomonas aeruginosa infection. Therefore this work will address the hypothesis that alternatively activatedmacrophages decrease pulmonary inflammation in P. aeruginosa infection and that this is dependent upon production of TGF and arginase-1. We will utilize a model of P. aeruginosa pneumonia in normal and genetically engineered mice to address 3 distinct aims. Aim 1 will determine whether regulation of inflammation caused by P. aeruginosa lung infection is dependent upon alternative macrophage activation. Aim 2 will address whether AAM regulation of T cell disposition can control inflammation and lung damage through the production of TGF. Aim 3 will determine whether arginase-1 expression by macrophages is required to prevent inflammation induced by P. aeruginosa pneumonia. Mouse models with genetically altered AAM TGF signaling and macrophage-specific arginase-1 production will be used along with adoptive transfer methodologies and complementary in vitro experiments. The impact of these alterations will be evaluated in terms of inflammation classical macrophage function and T cell subset activation and function to determine the important mechanisms employed by macrophages in regulating these responses. Highlighting the clinical relevance of this work is the use of the antimicrobial agent azithromycin as an immunomodulator in patients with CF. This drug has been shown to slow pulmonary function decline and decrease morbidity in CF patients infected with Pseudomonas but the beneficial mechanistic effect is unknown. Recently it has been shown in both in vitro and animal studies that azithromycin polarizes macrophages to an alternative-like phenotype dramatically increasing the expression of arginase-1. This data along with the successful long-term use of azithromycin in patients with CF make studying the role of alternative macrophage activation in response to Pseudomonas pneumonia attractive and likely to yield novel therapeutic targets for intervention to alter this destructive cycle of inflammation and airway damage.

project_terms:
Acute;Address;Adoptive Transfer;Affect;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Azithromycin;Bacterial Infections;Bacterial Pneumonia;Cell physiology;Cells;Characteristics;Chronic;Chronic lung disease;Cystic Fibrosis;Data;Disease;Exposure to;Future;Genes;Genetically Engineered Mouse;Goals;Gram-Negative Bacterial Infections;Homeostasis;Immune;Immune response;Immunomodulators;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Knowledge;Lead;Life;Lung;Lung Inflammation;Macrophage Activation;Methodology;Methods;Modeling;Morbidity - disease rate;Mouse Strains;Mus;Organism;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Play;Pneumonia;Process;Production;Pseudomonas;Pseudomonas aeruginosa;Pseudomonas aeruginosa pneumonia;Pulmonary Inflammation;Pulmonary Pathology;Randomized Clinical Trials;Regulation;Role;Series;Signal Transduction;Staging;T cell differentiation;T cell regulation;T-Lymphocyte;T-Lymphocyte Subsets;Time;Transforming Growth Factors;Up-Regulation;Work;airway inflammation;antimicrobial drug;arginase;base;cell mediated immune response;clinically relevant;cystic fibrosis mouse;cystic fibrosis patients;cytokine;evidence base;experience;extracellular;functional decline;in vivo;macrophage;mortality;mouse model;neutrophil;new therapeutic target;pathogen;prevent;pulmonary function decline;repaired;research study;response;therapeutic target

public_health_relevance:
Cystic fibrosis and other chronic lung diseases cause progressive life-threatening lung destruction due in part to excessive inflammation with frequent exacerbations caused by repeated bacterial infections. This project will investigate the regulatory role that macrophages play in the immune response to Pseudomonas aeruginosa one of the most common bacterial pathogens in these patients. This work will lead to the identification of therapeutic targets for intervention to delay the rate of pulmonary decline in these patients.


application_id: 9088191
project_number: 4U01AA021901-05
project_title: Novel therapies in alcoholic hepatitis University of Louisville
administering_ic: NIAAA
award_notice_date: 2016-06-22
opportunity_number: RFA-AA-12-007
application_type: 4
activity_code: U01
ic: AA
serial_number: 021901
program_official: WANG, JOE
project_start_date: 2012-09-15
project_end_date: 2018-06-30
study_section: ZAA1-JJ(07)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
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): This application is the translational component of an overall UO1 application entitled "Novel therapies in alcoholic hepatitis - University of Louisvill." Alcoholic hepatitis (AH) has a high morbidity and mortality. In VA Cooperative Studies in which liver biopsies were performed only 35% of patients with AH and underlying cirrhosis and 60% of those with AH alone (no cirrhosis) were alive at the end of four years with most deaths occurring early in the study. There is no FDA-approved therapy for any stage of alcoholic liver disease (ALD). The most widely-used (off-label) drug therapies for AH are glucocorticoids and pentoxifylline. Both agents have anti-inflammatory activities and downregulate proinflammatory cytokines such as tumor necrosis factor (TNF). Unfortunately an important subset of AH patients treated with glucocorticoids have "steroid resistance" and some patients have contraindications to steroid therapy. Studies on pentoxifylline in AH are limited and efficacy appears highest in preventing/treating the hepatorenal syndrome. Thus new therapies as well as a better understanding of mechanisms/biomarkers for severity of disease and response to therapy are necessary. Our research team has been a leader in defining mechanisms of alcohol-induced liver injury using in vitro and animal models of ALD and in translating basic findings into the clinical setting. Our group is the first to describe dysregulated cytokine metabolism in AH. We have a long-standing interest in mechanisms of inflammation and liver injury. We also have extensive experience in the gut-liver axis and AH as well as in the development of novel therapies for AH.!!Building on the above translational research strengths of our program which focus on the gut-liver axis and inflammation in ALD we propose three highly translational Specific Aims which all relate to and utilize samples from our proposed UO1 clinical trial. Aim 1 will evaluate novel mechanisms for alcohol-induced alterations in gut integriy leading to endotoxemia and AH. We will study the therapeutic efficacy of both live probiotics and probiotic supernatants. Aim 2 will study the role of specific PDE4 inhibition in AH using animal models and our AH clinical patient population. There are recent data in the pulmonary literature showing that specific PDE4 inhibitors are effective in steroid resistant patients which may translate to AH. Lastly Aim 3 evaluates mechanisms for steroid resistance using both specimens from patients in our clinical trial and in vitro data. All three of our specific aims utiize specimens obtained from our U01 clinical trial and our protocol interacts with the two other translational protocols in our U01 consortium. Our goal is not only to better understand mechanisms for AH but also to develop new therapies (including those already available for other diseases) for AH either immediately transforming clinical practice or providing novel therapies for our clinical trial consortium.

project_terms:
Acute Alcoholic Hepatitis;Adenylate Cyclase;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Amino Acids;Anabolic steroids;Animal Model;Anti-Bacterial Agents;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Bacteria;Biological Assay;Biological Markers;Cessation of life;Cirrhosis;Clinical;Clinical Trials;Cyclic AMP;Data;Development;Dinoprostone;Disease;Effectiveness;Endotoxemia;Endotoxins;FDA approved;Glucocorticoids;Goals;Hepatorenal Syndrome;Human;Hypoxia;Hypoxia Inducible Factor;In Vitro;Inflammation;Interleukin-1;Interleukin-10;Intestines;Label;Laboratories;Life;Literature;Liver;Lung;Metabolism;Misoprostol;Morbidity - disease rate;Mucins;Mucous body substance;Nutritional Support;Patients;Pentoxifylline;Peptides;Permeability;Pharmacotherapy;Phosphodiesterase Inhibitors;Placebos;Positioning Attribute;Prednisone;Probiotics;Production;Prognostic Marker;Protocols documentation;Research;Research Personnel;Resistance;Role;Sampling;Severities;Severity of illness;Signal Transduction;Site;Specimen;Staging;Steroid Resistance;Steroid therapy;Steroids;Stimulus;Supplementation;TNF gene;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Translating;Translational Research;Treatment Efficacy;Universities;Zinc supplementation;analog;clinical practice;cooperative study;cytokine;experience;improved;inhibitor/antagonist;interest;liver biopsy;liver injury;monocyte;mortality;novel;novel strategies;novel therapeutics;patient population;peripheral blood;phosphoric diester hydrolase;prevent;probiotic therapy;programs;response;response biomarker;trefoil factor

public_health_relevance:
This is a translational application portion of an overall UO1 application. Our goal is not only to better understand mechanisms for AH but also to develop new therapies (including those already available for other diseases) for AH.


application_id: 9088110
project_number: 4R01CA091901-14
project_title: Novel aureolic acid type antitumor agents
administering_ic: NCI
award_notice_date: 2016-06-29
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: CA
serial_number: 091901
program_official: FU, YALI
project_start_date: 2001-06-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-BCMB-B(02)M]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
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:
DESCRIPTION (provided by applicant): Aureolic acid-type anticancer agents such as mithramycin (MTM) chromomycin (CMM) and durhamycin (DHM) are potent anticancer and anti-HIV drugs with a unique mode-of-action. They inhibit the growth of cancer cells by cross-linking GC-rich DNA thereby shutting down specificity-protein (Sp)-dependent pathways toward various proto-oncogenes including c-myc and c-src the latter being associated with the unique hypocalcemic activity found for these drugs. Particularly MTM is important and has become a popular biochemical tool to study Sp-dependent signal transduction pathways but -due to its toxic side effects- is rarely used as anticancer agent except for the treatment of tumor hypercalcemia refractory to other chemotherapy. However MTM was identified in 2011 by the NCI as the only lead from a screen of 50000 compounds that inhibits the EWS-FLI1 transcription factor responsible for the highly malignant phenotype of Ewing sarcomas which often affect children and were untreatable for the past 40 years. In addition another NCI group found in June 2012 that MTM represses cigarette smoke induced ABCG2 efflux pumps responsible for the drug resistance of lung and esophageal cancers and inhibited multiple stem-cell related pathways relevant for tumorigenicity and proliferation of such cancers. A few years ago MTM was identified as a potential lead drug against neurological diseases arthritis and for the treatment of hematologic disorders. All these new applications require only very small less toxic concentrations of the drug although the mode-of-action in these contexts remains obscure particularly the mode affecting the EWS-FLI1 transcription factor. MTM's biosynthesis has been studied intensely during the previous funding periods of this research project and consequently pursued combinatorial biosynthetic efforts revealed various biosynthetic intermediates and many new MTM-analogues which allowed deducing important structure-activity-relationships. Two regions are of special interest: First a modification of the 3-side chain first exemplified in the superior analogues MTM SK and MTM SDK led to much better anticancer activity profiles with a greatly improved therapeutic index compared to MTM itself. Second exchange of the D-mycarose sugar in E-position of MTM's trisaccharide chain by D-digitoxose led to superior analogues with greatly reduced toxic side effects. This now allows for new strategies to further concentrate on these regions of the molecule for further drug optimization.  During the previous biosynthetic studies biosynthetic intriguing and interesting keyenzymes were discovered which need to be further investigated particularly the co-dependent enzymes MtmGIV/MtmC (bifunctional glycosyltransferase/methyltransferase-ketoreductase) MtmOIV/MtmW (C-C-bond cleaving oxygenase/ketoreductase) which play key roles for the 3-side chain and the trisaccharide chain formation. Furthermore the PKS release remains unclear and it is hypothesized that another co-dependent enzyme pair namely oxygenase MtmOII and cyclase MtmX play an important role for this process. The goal here is to gain a deeper understanding of the biosynthetic roles mechanisms and interactions of these key enzymes of the MTM pathway to pave the way for the optimization and re-engineering of these enzymes that are crucial for novel further improved MTM derivatives. It is planned to (a) further investigate unclear biosynthetic steps and mechanisms of the MTM and other aureolic acid pathways (b) to further develop strategies for the selective generation of new improved MTM analogues including selective 3-side chain and sugar exchange/glycorandomization strategies (c) to analyze intriguing enzymes particularly recently discovered co- dependent enzyme pairs. New resulting MTM analogues will be submitted to the NCI DTP (developmental therapeutics program) for further mechanistic investigations.

project_terms:
ABCG2 gene;Address;Adverse effects;Affect;Anabolism;Anti-HIV Agents;Antineoplastic Agents;Arthritis;Biochemical;Cancer Cell Growth;Child;Cleaved cell;DNA;Developmental Therapeutics Program;Disease;Drug resistance;EWS-FLI1 fusion protein;Engineering;Enzymatic Biochemistry;Enzymes;Ewings sarcoma;Funding;Generations;Goals;Health;Hypercalcemia;Investigation;Lead;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Methods;Methyltransferase;Modification;Natural Products;Oxygenases;Pathway interactions;Pattern;Pharmaceutical Preparations;Play;Plicamycin;Positioning Attribute;Process;Production;Proteins;Proto-Oncogenes;Reaction;Refractory;Research;Research Project Grants;Role;SRC gene;Side;Signal Transduction Pathway;Specificity;Stem cells;Structure-Activity Relationship;Techniques;Therapeutic Index;Toxic effect;Trisaccharides;Tumorigenicity;Work;analog;anticancer activity;antitumor agent;base;biochemical tools;c-myc Genes;chemotherapy;chromomycin;cigarette smoke-induced;combinatorial;crosslink;design;digitoxose;drug modification;efflux pump;glycosylation;glycosyltransferase;improved;interest;malignant phenotype;mycarose;nervous system disorder;novel;protein structure;sugar;transcription factor;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed work aims to develop and refine a new generation of aureolic acid type natural product analogues with significantly diminished toxicity that will be useful as anticancer drugs and/or as drugs to treat neurological diseases arthritis and hematologic disorders. To enable the production of these fine-tuned drugs through combinatorial biosynthesis or chemo-enzymatic engineering in-depth research of the biosynthetic machinery of three aureolic acid pathways will be explored including key enzymes followed by enzyme re- engineering. In addition based on so far achieved structure-activity-relationship studies chemoenzymatic approaches for drug derivatization glycosylation exchange methods and chemoenzymatic glycorandomization techniques will be applied to selectively alter crucial structural features.


application_id: 9087317
project_number: 5R01HL123927-03
project_title: Crosstalk between membrane traffic proteins and integrin activation
administering_ic: NHLBI
award_notice_date: 2016-06-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 123927
program_official: CHANG, HENRY
project_start_date: 2014-09-25
project_end_date: 2018-06-30
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 8558885
contact_pi: LI, ZHENYU
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Platelets are central to hemostasis because they respond to vascular damage and secrete a variety of granule cargo molecules which are critical to thrombosis and its sequellae. Platelet secretion is a multistep process involving centralization of cytoplasmic organelles that provides a contractile force membrane fusion controlled by membrane traffic proteins and release of granule contents. The platelet integrin llb3 interacts with adhesive ligands such as fibrinogen and fibrin and mediates platelet adhesion and aggregation and thus plays a critical role in the development of thrombotic diseases such as heart attack and stroke. The overall goal of this proposal is to establish a link between the membrane traffic proteins and integrins that involve the two key events to platelet function platelet cargo release and integrin activation. VPS33B is a member of the Sec1/Munc18 protein family that has multiple roles in exocytosis. VPS33B is defective in patients with arthrogryposis renal dysfunction cholestasis (ARC) syndrome. Platelets from these patients lack -granules. In an attempt to define the roles of -granules in platelet functio and thrombosis we produced a mouse model of -granule deficiency in which VPS33B was deleted only in megakaryocytes and platelets. In Specific Aim 1 we will determine the roles of VPS33B in llb3-dependnet endocytosis and llb3 outside-in signaling. -granule contents vWF and fibrinogen are significantly reduced in the platelets lacking VPS33B. Surprisingly VPS33B-/- platelets fail to retract a clot and are defective in spreading on fibrinogen. Using the CHO recombinant llb3 activation model we showed that overexpression of VPS33B markedly potentiates cell spreading on fibrinogen and actin polymerization. Thus we hypothesize that in platelets there exists a crosstalk between the membrane traffic proteins and integrin activation and that VPS33B is a key contributor to llb3 outside-in signaling. This hypothesis will be tested using the platelet- specific VPS33B conditional knockout mice and other VPS33B knockout mice such as whole-body knockout mice and a Chinese Hamster Ovary (CHO) integrin activation model. Our preliminary data demonstrated that VPS33B co-localizes with llb3 as detected by confocal microscopy and forms a complex with llb3 as detected by co-immunoprecipitation. In Specific Aim 2 we will use multiple approaches to characterize the binding determinants in VPS33B and the 3 cytoplasmic domains for each other. In Specific Aim 3 we will identify the molecular mechanisms of VPS33B-dependent llb3 outside-in signaling. Completion of these studies will not only identify a novel llb3 binding partner that plays an important role in llb3 outside-in signaling but also for the first time establish a lin between membrane traffic proteins and integrin activation in platelets.

project_terms:
Actins;Acute;Adhesions;Adhesives;Alpha Granule;Anabolism;Arthrogryposis;Atherosclerosis;Binding;Binding Proteins;Biochemical;Blood Platelets;Blood Vessels;Cause of Death;Cell Adhesion;Cell surface;Cells;Chinese Hamster;Chinese Hamster Ovary Cell;Cholestasis;Co-Immunoprecipitations;Coagulation Process;Complex;Confocal Microscopy;Cytomegalovirus;Cytoplasmic Granules;Cytoplasmic Organelle;Cytoplasmic Tail;Data;Defect;Development;Disease;Endocytosis;Epitopes;Event;Exocytosis;Extracellular Matrix;Fibrin;Fibrinogen;Functional disorder;Goals;Health;Hemostatic function;Host Defense;Human;Inflammation;Integrin Binding;Integrin beta Chains;Integrins;Kidney;Knockout Mice;Ligands;Link;MAP Kinase Gene;Malignant Neoplasms;Maps;Mediating;Megakaryocytes;Membrane Fusion;Membrane Protein Traffic;Membrane Proteins;Modeling;Molecular;Mouse Strains;Mus;Myocardial Infarction;Ovary;P-Selectin;Pathway interactions;Patients;Phosphorylation;Plasma;Platelet Activation;Play;Process;Protein Family;Proteins;Recombinants;Research Project Grants;Role;SRC gene;Signal Pathway;Signal Transduction;Syndrome;Testing;Thrombosis;Time;United States;VWF gene;Work;Wound Healing;angiogenesis;antimicrobial;base;extracellular;in vivo;insight;member;mouse model;mutant;novel;overexpression;polymerization;prevent;promoter;receptor;receptor mediated endocytosis;recombinase;research study;rho GTP-Binding Proteins;stem;stroke;syntaxin binding protein 1

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Blood platelets are essential for acute thrombotic events such as heart attacks and strokes and also contribute to local and systemic inflammation. This research project seeks to understand how the membrane traffic proteins such as VPS33B regulate platelet integrin activation and thrombosis. Completion of the work will provide new insights into pathways that could be targeted to prevent and treat arterial thrombosis a leading cause of death in the United States.


application_id: 9086299
project_number: 5R01CA187273-02
project_title: Suppression of Prostate Tumor Growth and Metastasis by Inhibition of Vimentin
administering_ic: NCI
award_notice_date: 2016-06-06
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 187273
program_official: CHEN, WEIWEI
project_start_date: 2015-07-01
project_end_date: 2020-06-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
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:
Androgens;Apoptosis;Apoptotic;Binding;Biology;Cancer Etiology;Cell Culture Techniques;Cell Surface Receptors;Cells;Cessation of life;Chemicals;Conditioned Culture Media;Development;Epithelial;Epithelial Cells;Family;Fibroblasts;GRP78 gene;Growth;Health;Human;Impaired wound healing;Inhibition of Apoptosis;Killings;Knockout Mice;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Mesenchymal;Metastatic Neoplasm to the Lung;Modeling;Molecular Target;Mus;Neoplasm Metastasis;Normal Cell;Organ;PAWR protein;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phenotype;Primary Neoplasm;Prostate;Prostate Cancer therapy;Prostatic Neoplasms;Proteins;Quinolones;Resectable;Resistance;Role;Structure-Activity Relationship;Surface;Testing;Therapeutic;Tissues;Toxic effect;Tumor Suppressor Proteins;Vimentin;analog;bone;cancer cell;cell motility;conventional therapy;deprivation;extracellular;in vivo;insight;member;men;metastatic process;mouse model;nanomolar;novel;paracrine;prostate cancer cell;prostate cancer model;quinoline;receptor;response;screening;small molecule;therapy resistant;tumor;tumor growth;tumor xenograft


application_id: 9085186
project_number: 4R01AG045833-04
project_title: Circadian rhythms and melatonin signaling in the aging gastrointestinal system
administering_ic: NIA
award_notice_date: 2016-05-30
opportunity_number: RFA-AG-13-007
application_type: 4
activity_code: R01
ic: AG
serial_number: 045833
program_official: MACCHIARINI, FRANCESCA
project_start_date: 2013-08-15
project_end_date: 2018-05-31
study_section: ZAG1-ZIJ-5(M2)
contact_pi_person_id: 1862567
contact_pi: CASSONE, VINCENT M
other_pis: Not Applicable
congressional_district: 06
department: 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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Biological circadian clocks are fundamental properties of all living organisms studied in any detail. In animals clocks regulate the timing of sleep: wake cycles as well as the coordination of internal body functions such as temporal variations in temperature hormone levels aspects of disease and gastrointestinal physiology. The molecular bases for biological rhythms are at least in part regulated by the expression of "clock genes" a group of genes whose complex interactions govern 24-hour rhythms. Work in our lab has demonstrated that clock genes are important in the regulation of colonic motility: the mouse colon possesses a functional circadian clock that regulates rhythms of a wide array of genes as well as intestinal motility. Further we have shown that the colonic clock regulates multiple downstream processes associated with normal intestinal motility absorption cell proliferation and cell signaling as well as potential pathological processes. In addition in mammals there is a hierarchical organization in which a central pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) coordinates multiple peripheral processes as well as entrains the entire system to the light: dark cycle (LD) through specialized photic pathways. Our general hypothesis is that the global regulation of gastrointestinal circadian rhythms involves the complex bi-directional interaction of central SCN clockworks and intestinal clocks themselves and that disruption of any of these predisposes us to disease. The overall objective of this proposal is to determine the underlying mechanism through which colonic motility varies with the time of day under normal circumstances and to determine the consequences of aging on circadian patterns of colonic motility. Our hypothesis is that one factor mediating changes in intestinal function during aging is the circadian secretion of the hormone melatonin by the pineal gland and by intestinal tissues themselves. We will therefore ask what aspects of gastrointestinal rhythms are affected by normal aging (Specific Aim 1). We will then ask whether pineal melatonin influences gastrointestinal rhythmicity in young vs aged mice at several levels of biological organization. Finally we will ask whether interference in the production of melatonin affects aging aspects of gastrointestinal rhythmicity by comparing melatonin deficient strains of mice (C57/Bl6) with strains of mice capable of producing melatonin cycles (C3H) and whether these processes are dependent the known melatonin receptor molecules by comparing wild-type with MT1 receptor MT2 Receptor and MT2/MT2 receptor knockout mice.

project_terms:
Acetylcholine;Address;Affect;Age;Aging;Aging-Related Process;Animals;Biological;Biological Rhythm;Cell Proliferation;Circadian Rhythms;Colon;Complex;Data;Disease;Exhibits;Future;Gastrointestinal Physiology;Gene Expression;Gene Expression Profile;Genes;Harvest;Health;Hormones;Hour;Hypothalamic structure;In Vitro;Intestinal Motility;Intestines;Knock-out;Knockout Mice;Life;Light;Mammals;Measures;Mediating;Melatonin;Melatonin Receptors;Molecular;Mouse Strains;Mus;Muscle;Organism;Pacemakers;Pathologic Processes;Pathway interactions;Pattern;Periodicity;Peripheral;Phase;Physiological;Pineal gland;Process;Production;Property;Publishing;RNA;Receptor Melatonin MT1;Receptor Melatonin MT2;Regulation;Reporter;Role;Signal Transduction;Sleep Wake Cycle;System;Temperature;Testing;Time;Tissues;Variant;Wild Type Mouse;Work;absorption;aged;base;cell motility;circadian pacemaker;design;gastrointestinal;gastrointestinal function;gastrointestinal system;in vivo;interest;nano-string;normal aging;pressure;receptor;reduce symptoms;research study;response;suprachiasmatic nucleus

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Disruption of circadian clocks has deleterious effects on the health of most people especially among the aged and many of these issues are reflected in deteriorating gastrointestinal health. Further there is evidence that the pineal hormone melatonin may ameliorate symptoms associated with both sleep: wake cycles and gastrointestinal health in young and old people. This study will determine the mechanisms of circadian patterns of gastrointestinal gene expression and motility in young and old mice and will determine whether decreased melatonin signaling contributes to declining gastrointestinal health. The data may point to future treatments for normal but discomforting gastrointestinal health during aging.


application_id: 9084903
project_number: 2T32CA165990-04
project_title: Interdisciplinary Research Training in Cancer Biology
project_terms: Cancer Biology;Interdisciplinary Study;Research Training
administering_ic: NCI
award_notice_date: 2016-03-16
opportunity_number: PA-14-015
application_type: 2
activity_code: T32
ic: CA
serial_number: 165990
program_official: PERKINS, SUSAN N
project_start_date: 2013-04-01
project_end_date: 2021-03-31
study_section: Institutional Training and Education Study Section (F)[NCI-F (J1)]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: EVERS, BERNARD MARK
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
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
project_abstract:
DESCRIPTION (provided by applicant): Our interdisciplinary program will focus on training pre-doctoral students and post-doctoral fellows in cancer biology so they can effectively decipher important research questions associated with human cancer. We will accomplish this objective by integration of the already established and successful programs in Signal Transduction and Mechanisms of Cancer Cell Survival Cancer Progression and Metastasis Tumor Microenvironment Metabolomics and Oxidative Stress and DNA Damage with clinical exposure into one cohesive program. Trainees will receive both didactic and non-didactic instruction laboratory-based basic science research training in cancer research and cutting-edge clinical applications and career development as independent cancer biologists. To further their growth as important members of the scientific community students and fellows will receive ample training to articulate their ideas and communicate them effectively evaluate biomedical research and mentor others in scientific excellence.    
   
This program assembles a cohesive group of basic science and clinical faculty from 8 departments at the College of Medicine. In the past 10 years our program faculty trained 89 doctoral students and 95 post-doctoral students; our faculty have the experience and interdisciplinary focus to guide this group of trainees to function in research teams pursuing multidisciplinary investigations. We mentor trainees to be proficient at utilizing hypothesis-drive approaches as well as discovery-oriented research design to address key problems. All trainees are required to complete foundation courses in graduate-level Genetics Biochemistry Immunology Pharmacology Physiology Cell Biology Molecular Biology Biostatistics Ethics and Cancer Signaling and Cancer Biology and Therapy which emphasize cancer in the context of human disease. Training also involves participation in the weekly Markey Cancer Center Seminars a monthly Metastasis Journal Club and a monthly Cancer Biology Journal Club. A unique feature of this program is the interdisciplinary training emphasizing bench to bedside (and vice versa) research topics to provide a bridge between the fundamental biology of cancer and clinical cancer. The ultimate objective is to develop a cadre of future scientists who can become leaders in integrative team approaches and understand the complex issue of cancer as it relates to potential prevention and treatment strategies. To help ensure our commitment to the clinical translation of basic science discoveries Markey Cancer Center Associate Director Vivek Rangnekar Ph.D. and Director B. Mark Evers M.D. will continue to be PIs for this team-based training program. The University of Kentucky places a significant emphasis on training minority students post-doctoral researchers and physicians and this program will continue to ensure the inclusion of individuals with under-represented racial and ethnic background to better serve our diverse society. Accordingly this training program will train the next generation of cancer researchers to better understand and treat cancers using an interdisciplinary team approach.


