# projects

application_id: 7892501
project_number: 5R01GM083187-02
project_title: Regulation of alternative pre-mRNA processing by small nucleolar RNAs
administering_ic: NIGMS
award_notice_date: 2010-07-12
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 083187
program_official: BENDER, MICHAEL T
project_start_date: 2009-08-01
project_end_date: 2013-07-31
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
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): There is a fundamental gap in understanding the function of small RNAs that constitute a large part of human gene expression. For example we do not know how the loss of small nucleolar RNA (snoRNA) expression contributes to the Prader-Willi syndrome the most frequent genetic cause for life-threatening obesity. Our long-term goal is to elucidate the regulation of alternative splicing by small RNAs that are estimated to comprise more than 40% of human gene expression. The objective of this application is to determine which alternative splicing patterns are influenced by the snoRNAs missing in individuals with Prader-Willi syndrome and to understand the molecular basis by which one of these snoRNAs HBII-52 influences alternative splicing patterns. The central hypothesis is that snoRNAs missing in individuals with Prader- Willi syndrome regulate alternative splicing by masking splicing regulatory elements on pre- mRNAs. Thus these snoRNAs regulate expression of numerous genes by changing their alternative splicing patterns. The rationale for the proposed research is that the genes regulated by these snoRNAs represent drug targets for treatment of the Prader-Willi syndrome. This proposal is therefore relevant to the NIH's mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human disease. Guided by our first published report that the snoRNA HBII-52 influences alternative splicing and additional strong preliminary data this hypothesis will be tested by pursuing two specific aims: 1) Identify the pre-mRNAs that are regulated by the snoRNAs missing in people with Prader-Willi syndrome; and 2) Determine how HBII-52 regulates alternative splice site usage and test alternatives for its expression. Under the first aim changes in pre-mRNA processing will be determined after ectopically expressing individual snoRNAs using bioinformatic predictions and splice-site sensitive DNA arrays. Under the second aim we will identify the repressor activity that competes with the snoRNA HBII-52 and determine its mode of action using an established in vitro system. The proposed work is innovative because it shows a complete new role for snoRNAs in the regulation of alternative pre-mRNA splicing. It may well change the current `textbook knowledge' that snoRNAs only regulate non-mRNAs. The proposed research is significant because it would show a novel role of snoRNAs identify the molecular defects in Prader-Willi syndrome and help to predict the influence of small RNAs on splice site selection.  
  
PUBLIC HEALTH RELEVANCE: The proposed studies delve into an under-investigated area of gene expression and have the potential applicability to understand the molecular cause of the Prader-Willi Syndrome and potentially other forms of inherited obesity. The proposed research is relevant for public health because it investigates a new mechanism of human gene expression. Understanding this mechanism is the basis to improve diagnostics and therapeutic options for human diseases caused by defects in pre-mRNA processing.

project_terms:
Affinity;Alternative Splicing;Area;Binding (Molecular Function);Biochemical;Bioinformatics;Biology;Boxing;Cell Culture Techniques;Code;Collaborations;Complex;DNA;Data;Defect;Diagnostic;Drug Delivery Systems;Exons;Failure (biologic function);Fostering;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genome;Goals;Human;In Vitro;Individual;Inherited;Knockout Mice;Knowledge;Life;Link;Masks;Mass Spectrum Analysis;Messenger RNA;Methods;Mission;Molecular;Molecular Target;Obesity;Orphan;Outcome;Pattern;Peptide Nucleic Acids;Peptides;Prader-Willi Syndrome;Process;Property;Proteins;Publishing;RNA;RNA Sequences;RNA Splicing;Receptor Serotonin 5-HT2C;Regulation;Regulatory Element;Reporter Genes;Reporting;Research;Resources;Ribosomal RNA;Role;SNRPN;Science;Site;Small Nuclear RNA;Small Nucleolar RNA;Small RNA;System;Techniques;Testing;Textbooks;Therapeutic;Transcript;Transfer RNA;Work;base;human disease;improved;in vivo;innovation;mRNA Precursor;novel;prevent;public health medicine (field);public health relevance;success

public_health_relevance:
Project narrativeThe proposed studies delve into an under-investigated area of gene expression and have thepotential applicability to understand the molecular cause of the Prader-Willi Syndrome andpotentially other forms of inherited obesity. The proposed research is relevant for public healthbecause it investigates a new mechanism of human gene expression. Understanding thismechanism is the basis to improve diagnostics and therapeutic options for human diseasescaused by defects in pre-mRNA processing.


application_id: 7892474
project_number: 5F30NS064669-02
project_title: Functional consequences of Notch-mediated angiogenesis following SCI
administering_ic: NINDS
award_notice_date: 2010-07-27
opportunity_number: PA-05-151
application_type: 5
activity_code: F30
ic: NS
serial_number: 064669
program_official: OWENS, DAVID F
project_start_date: 2009-07-01
project_end_date: 2012-06-30
study_section: NST-2 Study Section [NST-2]
contact_pi_person_id: 9401645
contact_pi: FASSBENDER, JANELLE M
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Traumatic spinal cord injury (SCI) is complicated by secondary pathology that increases tissue loss and exacerbates functional recovery beyond the initial physical impact. Destruction of the vasculature that supports spinal cord tissue compromises blood spinal cord barrier integrity and is a major impediment to tissue sparing and regeneration. While formation of new blood vessels occurs robustly 3-7 days after contusive injury the vessels are leaky contributing to inflammation and edema. Thus it is unclear at this time whether neovascularization facilitates or impairs tissue loss and functional recovery. Notch signaling which is critical to vascular development and pathological angiogenesis is known to regulate vascular sprouting through formation of tip cells and to control endothelial cell proliferation. Importantly increased Notch signaling facilitates the maturation of vessels. Although fewer in number these vessels are larger less leaky and are capable of supporting growing tissue (Noseda et al. 2004; Harrington et al. 2007; Li et al. 2007). We hypothesize that by promoting the maturation of vessels formed 3-7 days post-SCI inflammation and tissue loss will be attenuated and functional recovery improved. Controlled proliferation with enhanced vessel maturation would provide evidence to control or attenuate angiogenic treatment in the first week following SCI. Conversely increased endothelial cell proliferation leading to a greater vascular density by 7 days post-SCI may relieve the ischemia and hypoxia that contributes to tissue loss. Moreover attenuation of the inflammatory response by decreasing pro-inflammatory activation of the microvascuiature may significantly impede repair processes. This observation would support the use of pro-angiogenic treatments that increase numbers of vessels in the absence of controlled permeability and enhanced blood spinal cord barrier integrity. Importantly it is critical to determine the impact the manipulation of Notch signaling has not only on the vasculature but also inflammation and tissue loss due to secondary pathology. PUBLIC HEALTH RELEVANCE:  Taken together it is expected that the proposed experiments will provide evidence not only to support the role of Notch in new blood vessel formation after SCI but facilitate studies that seek to target acute vascular responses to enhance functional locomotor recovery.

project_terms:
4-Hydroxy-Tamoxifen;Acute;Adult;Affect;Animals;Attenuated;Blood;Blood Vessels;Blood flow;Brain Hypoxia-Ischemia;Cell Proliferation;Cells;Cessation of life;Contusions;Data;Development;Dominant-Negative Mutation;Edema;Endothelial Cells;Ensure;Excision;Female;Galactosidase;Inflammation;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injury;Label;LacZ Genes;Lesion;Locomotor Recovery;Maintenance;Mediating;Mus;Natural regeneration;Outcome Measure;Pathologic Neovascularization;Pathology;Perfusion;Permeability;Process;Rattus;Recovery of Function;Regulation;Reporter;Role;Secondary to;Signal Transduction;Specificity;Spinal Cord;Spinal cord injury;Staining method;Stains;Testing;Thoracic spinal cord structure;Time;Tissues;Transgenes;Transgenic Mice;Trauma;angiogenesis;attenuation;cadherin 5;cell type;density;enhanced green fluorescent protein;improved;interest;neovascular;neovascularization;notch protein;prevent;public health relevance;repaired;research study;response;transgene expression;white matter


application_id: 7892430
project_number: 5R01EY014821-07
project_title: Mechanisms of Intermediate Distance Space Perception
administering_ic: NEI
award_notice_date: 2010-07-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 014821
program_official: WIGGS, CHERI
project_start_date: 2003-04-01
project_end_date: 2012-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Visual space perception in the intermediate distance range (2-25 meters) serves a multi-faceted function. It allows the observer to perceive the 3D shapes sizes and locations of objects orient in space and guides our actions. Yet despite its importance in enabling the observer to interact in the natural environment knowledge of the mechanisms underlying space perception in the intermediate distance is incomplete. The long-term objectives of this project are to understand the basic mechanisms of space perception and to discover how these mechanisms mediate human space perception and action. Pertaining to the ability to locate an object on the ground previous work found that the visual system achieves this by constructing a representation of the ground surface and then uses it as a reference frame to localize an object on the ground. To localize a suspended object requires determining the relative position between the suspended object and the ground reference frame. Recent empirical studies have provided critical evidence for the notion of a ground-based space perception and led to the discovery of several fundamental mechanisms for representing the ground surface. This progress has motivated the formulation of a more comprehensive theoretical framework for understanding how the visual system forms the ground-based perceptual space in the current proposal. The specific aims are to seek quantifiable empirical proofs to substantiate and advance the framework. The following three broadly defined issues will be investigated: A. The Perceptual Mechanisms Used by the SSIP to Represent the Ground and Other Surfaces B. The Role of Top-Down Processing in Space Perception C. Locating an Object that Does Not Have a Direct Surface Contact with the Ground The research will employ the psychophysical method to test human observers predominantly in the real 3D environment. In addition to complement the research performed in the real 3D environment the proposed project will investigate space perception in the virtual environment by capitalizing on the virtual reality technology. This approach is not only useful for controlling the experimental stimulation but will also yield insights into how one can improve the immersive quality of virtual scenes. Overall the findings and insights gained from the proposed project will advance the science of human space perception in the intermediate distance range. It will also improve our understanding of the visual problems confronted by people with compromised visual functions.  PUBLIC HEALTH RELEVANCE: Research of space perception in the intermediate distance is important because a significant proportion of our daily activity such as locomotion and navigating are performed over this distance range. Besides its contribution to perceptual sciences the knowledge gained from this project can provide insights into the space perception and action problems of patients with visual deficits (e.g. in strabismus and amblyopia) and the problems encountered by ordinary people in non-optimal visual environments. The approach of using the virtual reality technology in the proposed project has the potential of being adapted into a useful tool for aiding people with space perception deficits.

project_terms:
Address;Affect;Amblyopia;Attention;Binocular Vision;Characteristics;Complement;Cues;Depth Perception;Distance Perception;Drug Formulations;Effectiveness;Environment;Eye;Figs - dietary;Financial compensation;Funding;Goals;Human;Investigation;Knowledge;Learning;Link;Literature;Location;Locomotion;Measures;Mediating;Methods;Motion;Patients;Positioning Attribute;Process;Psychophysiology;Relative (related person);Research;Role;Sampling;Scanning;Science;Shapes;Source;Space Perception;Specific qualifier value;Strabismus;Surface;Technology;Testing;Texture;Vision;Vision Disparity;Visual;Visual system structure;Work;arm;base;improved;insight;meter;monocular;novel;operation;public health relevance;tool;virtual;virtual reality


application_id: 7892269
project_number: 5R01CA139843-03
project_title: MbSOD in chemotherapeutic-Induced Cardiac Injury
administering_ic: NCI
award_notice_date: 2010-07-19
application_type: 5
activity_code: R01
ic: CA
serial_number: 139843
program_official: FORRY, SUZANNE L
project_start_date: 2008-09-25
project_end_date: 2013-07-31
study_section: ZCA1-RPRB-O(J1)
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-08-01
project_abstract:
SPACE PROVIDED. Heart disease is a major dose limiting factor of cancer therapy that uses anthracycline as a componentof the protocol. Generation of reactive oxygen species (ROS) has been implicated in the toxicity of a largenumber of therapeutic agents including those containing the redox cycling groups. The goal of this study isto identify novel mechanisms that lead to cardioprotection during cancer treatment. Our studies of animaland isolated cardiomyocytes indicate that overexpression of the mitochondrial antioxidant enzymemanganese containing superoxide dismutase (MnSOD) protects the heart against adriamycin (ADR)-inducedcardiac injury. Interestingly ADR treatment leads to an increase in circulating levels of tumor necrosis factoralpha (TNF)t a pleiotropic cytokine that has also been shown to produce ROS. We also found that ADR-induced cardiac injury is associated with translocation of p53 to the mitochondria and interaction of p53 withMnSOD. Based on these novel findings we hypothesize that ADR toxicity is the result of a cascade thatinvolves ADR producing direct oxidative stress that sequentially leads to TNF production and amplification ofoxidative stress in mitochondria. To test this hypothesis cardiac tissue and cardiomyocytes isolated fromMnSOD deficient wild type and mice overexpressing MnSOD as well as p53 deficient p53 deficient withMnSOD deficient and p53 deficient overexpressing MnSOD mice of the same inbred background will beused as models. Aims 1 and 2 will test the hypothesis that ADR toxicity is the result of a cascade thatinvolves ADR and its metabolites producing direct oxidative stress that sequentially leads to TNF productionand amplification of oxidative stress in heart tissues and in cardiomyocytes. Aim 3 will test the hypothesisthat oxidative stress initiated in mitochondria serves as a death signal which regulates p53 translocation andits mitochondrial-mediated transcription dependent and independent pathways . Aim 4 will test thehypothesis that selective modulation of cellular antioxidant status or TNF levels alters ADR-induced cardiacnjury in experimental therapeutic settings. The results from these studies will provide important insights formechanistic-based pharmacological interventions to reduce cancer therapy-associated cardiac injury.Because the extensive use of ADR translation of these findings will not only improve the quality of life butwill also enhance the probability of cancer free survival for a large number of cancer patients.

project_terms:
ABCC1 gene;Acute;Adriamycin PFS;Animals;Anthracyclines;Antibodies;Antioxidants;Apoptosis;Biochemical;Biological Assay;Brain;Cancer Patient;Cardiac;Cardiac Myocytes;Cell Death;Cell Fractionation;Cessation of life;Chimeric Proteins;Chronic;Confocal Microscopy;Coupled;Data;Dose-Limiting;Drug Kinetics;Echocardiography;Enzymes;Gene Targeting;Generations;Genes;Genetic Transcription;Goals;Heart;Heart Diseases;Immunoprecipitation;Injury;Intervention;Kinetics;Knock-out;Knockout Mice;Lead;Link;Malignant Neoplasms;Manganese;Manganese Superoxide Dismutase;Mediating;Messenger RNA;Methods;Mitochondria;Modeling;Morphology;Mus;Nuclear;Oxidation-Reduction;Oxidative Stress;P-Glycoproteins;Pathway interactions;Plasma;Probability;Production;Proteins;Proteomics;Protocols documentation;Quality of life;Reactive Oxygen Species;Role;Signal Transduction;Source;Superoxide Dismutase;Superoxides;TP53 gene;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxic effect;Translations;Treatment Efficacy;Treatment Protocols;Treatment-Related Cancer;Tumor Necrosis Factor-alpha;Wild Type Mouse;adduct;base;cancer therapy;chromatin immunoprecipitation;clinical application;cytokine;improved;in vivo;insight;mimetics;morphometry;novel;overexpression;treatment effect;tumor


application_id: 7891247
project_number: 5R01HL073085-07
project_title: Angiotensin: A Link Between Obesity and Hypertension
administering_ic: NHLBI
award_notice_date: 2010-07-08
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 073085
program_official: THRASHER, TERRY N
project_start_date: 2003-06-03
project_end_date: 2013-06-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
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): Obesity is one of the most serious health problems in the United States and the most common cause of hypertension. Our laboratory demonstrated that adipocytes express components of the renin-angiotensin system (RAS) and that mice with diet-induced obesity and hypertension exhibit adipose-specific dysregulation of these components favoring an increase in blood pressure. Angiotensinogen (AGT) angiotensin type 1a receptors (AT1aR) and ACE2 are three components of the RAS that were regulated specifically in adipose tissue from mice with hypertension from diet-induced obesity. Preliminary data suggest that fatty acids enriched in the western high fat (HF) diet regulate specific RAS components in adipocytes serving as a mechanism for adipose-specific regulation of the RAS. We hypothesize that the RAS of adipocytes contributes to the development of obesity-induced hypertension. In aim 1 we hypothesize that adipose tissue is a predominant source for increased local and systemic angiotensin II (AngII) in obesity-hypertension. To test this hypothesis we will feed low fat (LF) or HF diets to mice with adipocyte-specific AGT deletion and determine the impact on the development of obesity-hypertension. In vitro studies will use adipose tissue from adipocyte AGT deficient mice to test the hypothesis that fatty acids regulate oxidative stress and proinflammatory adipokines through an AngII-dependent mechanism. In Aim 2 we hypothesize that adipocyte AT1aR mediate effects of local and/or systemic AngII to increase proinflammatory adipokine expression and promote obesity-hypertension. To test this hypothesis we will feed LF or HF diets to mice with adipocyte- specific AT1aR deficiency and determine the impact on the development of obesity-hypertension. In vitro studies will test the hypothesis that adipocyte AT1aR mediate effects of AngII to promote oxidative stress and adipokine expression. In Aim 3 we hypothesize that specific fatty acids regulate ACE2 expression and shedding to increase the development of obesity-hypertension. In vitro studies will define effects of specific fatty acids on ACE2 gene transcription and/or shedding in adipocytes and in vivo approaches will use ACE2 deficient mice to define their susceptibility to the development of obesity-hypertension. Results from these studies will identify dietary or pharmacologic sites for targeted reductions in the adipocyte RAS in the treatment of obesity-hypertension. PUBLIC HEALTH RELEVANCE: The relevance of this project to public health is the definition of mechanisms contributing to the development of hypertension in obese subjects. Given the epidemic of obesity in the US results from these studies will define whether an adipocyte renin-angiotensin system is a primary mechanism linking the epidemic of obesity to a growing prevalence of hypertension. Since the principal cause of death in obese patients is cardiovascular disease results from these studies are clinically significant.

project_terms:
Acids;Adipocytes;Adipose tissue;Adult;Angiotensin II;Angiotensin Type 1a Receptor;Angiotensinogen;Angiotensins;Blood Pressure;Body Weight;CCL2 gene;Cardiovascular Diseases;Cause of Death;Coupled;Data;Development;Diet;Epidemic;Exhibits;Fatty Acids;Fatty acid glycerol esters;Figs - dietary;Framingham Heart Study;Genetic Transcription;Health;Hypertension;In Vitro;Laboratories;Leptin;Link;Liver;Measures;Mediating;Mus;Obese Mice;Obesity;Overweight;Oxidative Stress;Patients;Predisposition;Prevalence;Production;Regulation;Relative (related person);Renin-Angiotensin System;Reporting;Site;Source;Testing;Therapeutic;Tissues;United States;Woman;Work;adipokines;clinically significant;feeding;in vivo;mRNA Expression;men;novel;obesity treatment;public health medicine (field);public health relevance;receptor;receptor coupling;resistin;response

public_health_relevance:
Project NarrativeThe relevance of this project to public health is the definition of mechanisms contributing to the development ofhypertension in obese subjects. Given the epidemic of obesity in the US results from these studies will definewhether an adipocyte renin-angiotensin system is a primary mechanism linking the epidemic of obesity to agrowing prevalence of hypertension. Since the principal cause of death in obese patients is cardiovasculardisease results from these studies are clinically significant.


application_id: 7891017
project_number: 3P20RR015576-10S1
project_title: Mechanisms of plasticity and repair after SCI
administering_ic: NCRR
award_notice_date: 2009-08-23
opportunity_number: RFA-RR-04-008
application_type: 3
activity_code: P20
ic: RR
serial_number: 015576
suffix: S1
program_official: GOROSPE, RAFAEL
project_start_date: 2009-08-24
project_end_date: 2010-08-23
study_section: ZRR1-RI-8(02)
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source
and thus could be represented in other CRISP entries. The institution listed is
for the Center which is not necessarily the institution for the investigator.
To expand the imaging core capabilities through the addition of a Live Cell Imaging System. This will greatly accelerate several Centers of Biomedical Research Excellence- sponsored projects.


application_id: 7890580
project_number: 5R37DK039176-23
project_title: Regulation of lipoprotein lipase in adipocytes
administering_ic: NIDDK
award_notice_date: 2010-06-28
application_type: 5
activity_code: R37
ic: DK
serial_number: 039176
program_official: HAFT, CAROL R
project_start_date: 1988-09-01
project_end_date: 2011-07-31
study_section: Cellular Aspects of Diabetes and Obesity Study Section[CADO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
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
budget_start_date: 2010-07-01
project_abstract:
DESCRIPTION (provided by applicant): The mechanism of LPL regulation is complex and we have focused on the translational regulation of LPL which occurs in response to diabetes and in response to hormones such as thyroid hormone and epinephrine. LPL translation is controlled by an RNA binding complex that forms in response to epinephrine and binds to the 3'UTR of the LPL mRNA resulting in an inhibition of LPL translation. One component of this complex is a member of the A-Kinase Anchoring Protein (AKAP) family which tethers PKA to specific cellular sites. AKAP121 contains a consensus KH RNA binding region and is a component of the RNA binding complex. Additional studies have characterized the region on the LPL mRNA that binds the AKAP- PKA complex and demonstrated that transgenic mice expressing LPL without the proximal 3'UTR upregulate LPL at the translational level. Therefore we plan to examine LPL translation regulation by studying both the RNA binding complex and the LPL mRNA. Hypothesis 1. LPL translation is regulated by an RNA binding complex which interacts with a specific motif on the LPL 3'UTR. This RNA binding complex depends on specific sequence elements of PKA AKAP149 and possibly other components. Aim 1. Examine AKAP149/121 interactions with other elements of the PKA complex. Aim 2. Determine whether AKAP targeting to ER or mitochondria is important in LPL translation inhibition. Aim 3. Will the introduction of AKAP149 confer LPL translational inhibition by PKA in a non-adipose cell? Aim 4. Is the increase in LPL that accompanies hypothyroidism due to changes in AKAP expression? Aim 5. Identify LPL 3'UTR sequence elements that alter the interaction with the RNA binding complex. Hypothesis 2. By preventing the interaction between the RNA binding complex with the LPL 3'UTR LPL will become unresponsive to epinephrine and adipose tissue will accumulate more lipid diverting lipid from other insulin target organs yielding improved insulin sensitivity. Aim 6. Examine the phenotype of a transgenic mouse that expresses LPL lacking the proximal 3'UTR. Will this cause lipid partitioning into adipose tissue and improve insulin sensitivity? Aim 7. Examine insulin sensitivity and other phenotypic features of d-AKAP1 knockout mice. Relevance. LPL is a central enzyme in lipid metabolism: the enzyme is expressed by adipocytes and muscle cells and hydrolyzes the triglyceride core of plasma VLDL and chylomicrons. LPL is an important adipogenic enzyme in adipose tissue and abnormalities in LPL result in inefficient lipoprotein metabolism leading to atherosclerosis especially in patients with diabetes.

project_terms:
3' Untranslated Regions;A kinase anchoring protein;Abbreviations;Accounting;Acetates;Adipocytes;Adipose tissue;Atherosclerosis;Binding (Molecular Function);Blood capillaries;Brown Fat;Catabolism;Chylomicrons;Complex;Consensus;Cyclic AMP-Dependent Protein Kinases;Development;Diabetes Mellitus;Elements;Endoplasmic Reticulum;Endothelium;Enzymes;Epinephrine;Epitopes;Esterified Fatty Acids;Gene Expression Regulation;Homologous Gene;Hormones;Human;Hydrolysis;Hypothyroidism;Insulin;Knock-out;Knockout Mice;Lead;Lipids;Lipoproteins;Messenger RNA;Metabolism;Mitochondria;Mus;Muscle Cells;Nucleotides;Organ;Patients;Phenotype;Physiological;Plasma;Protein Family;Proteins;RNA Binding;RNA Splicing;RNA-Binding Proteins;Regulation;Research Personnel;Site;Thyroid Hormones;Tissues;Transgenes;Transgenic Mice;Translational Regulation;Translational Repression;Translations;Triglycerides;Triiodothyronine;Untranslated Regions;Very low density lipoprotein;base;capillary;genetic manipulation;improved;insulin sensitivity;lipid metabolism;lipoprotein lipase;member;overexpression;prevent;programs;protein expression;response


application_id: 7890507
project_number: 5R01CA140991-02
project_title: Targeting Glucose Metabolism in Cancer
administering_ic: NCI
award_notice_date: 2010-04-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 140991
program_official: SPALHOLZ, BARBARA A
project_start_date: 2009-07-01
project_end_date: 2014-04-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 9475582
contact_pi: TELANG, SUCHETA
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): A high rate of glycolytic flux even in the presence of oxygen is a central metabolic hallmark of neoplastic tumors. Cancer cells preferentially utilize glycolysis in order to satisfy their increased energetic and biosynthetic requirements. This metabolic phenotype is confirmed by positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-glucose which demonstrates that tumors take up 10-fold more glucose than adjacent normal tissues in vivo. Over-expression of HIF-1a and myc ras activation and loss of p53 function stimulate glycolysis by activating a family of four bifunctional 6-phosphofructo-2-kinase/fructose-26-bisphosphatases (PFKFB) which synthesize fructose-26-bisphosphate (F26BP) an allosteric activator of 6-phosphofructo-1- kinase (PFK-1) which is an essential control point in the glycolytic pathway. The PFKFB enzymes are encoded by four genes (PFKFB1-4) reportedly expressed in distinct tissues: liver/skeletal muscle (PFKFB1) heart (PFKFB2) placenta (PFKFB3) and testis (PFKFB4). Previous studies have focused on the PFKFB3 isozyme as the dominant source of F26BP in neoplastic cells due to its high kinase:phosphatase ratio (~740:1) and overexpression in multiple tumors. The identification of the specific PFKFB isozyme responsible for the high rate of glycolysis in cancer cells may allow for the development of novel agents that suppress tumor growth through inhibition of glycolysis. In preliminary studies we measured mRNA expression of the four PFKFB isozymes in 20 tumor tissues by multiplex RT-PCR and found that PFKFB4 mRNA (and not PFKFB3) was markedly increased in 17/20 tumors relative to adjacent normal tissues. We speculated that the high PFKFB4 expression may be caused by disparate oncogenic pathways converging to enhance glycolytic flux. We found that hypoxic exposure of K-rasG12S+ A549 lung adenocarcinoma cells and introduction of H-rasG12V into immortalized human bronchial epithelial cells increased PFKFB4 mRNA and protein expression. Further cell fractionation revealed that the PFKFB4 protein and not PFKFB3 localized to the cytoplasm the cellular compartment of both PFK-1 and glycolysis. Last transient siRNA silencing of PFKFB4 mRNA expression in K- rasG12S+ A549 cells decreased steady-state concentration of F26BP glycolytic flux and anchorage- independent tumor growth in mice. Taken together these preliminary studies provide rationale for further investigation of the PFKFB4 isozyme as a possible novel target for the development of anti-neoplastic agents. We hypothesize that the PFKFB4 isozyme is required for the high glycolytic flux survival growth and spread of transformed cells. We plan to test this hypothesis by pursuing the following specific aims: 1. To examine the requirement for F26BP synthesized by PFKFB4 for glycolytic and mitochondrial metabolism. 2. To determine the requirement for F26BP synthesized by PFKFB4 for growth invasiveness and survival of normal immortalized and ras-transformed epithelial cells. 3. To examine the effect of PFKFB4 genomic deletion on growth and metabolism of ras-dependent tumors in vivo using a Cre-lox inducible mouse knockout of PFKFB4. PUBLIC HEALTH RELEVANCE: We anticipate that shRNA silencing or genomic deletion of the PFKFB4 isozyme will attenuate the neoplastic potential of transformed epithelial cells and conversely that increased F26BP (from overexpression of PFKFB4) will enhance glycolytic flux and augment tumor growth. These findings may validate PFKFB4 as a new target for the inhibition of glycolysis. Accordingly suppression of glycolytic flux in cancer via the development of small molecule inhibitors of PFKFB4 through computational screening for competitive inhibitors of the PFKFB4 substrate-binding domain may reduce the high mortality that is associated with cancer.

project_terms:
6-Phosphofructokinase;A549;Actins;Adenocarcinoma Cell;Age-Months;Anchorage-Independent Growth;Apoptosis;Attenuated;Basement membrane;Binding (Molecular Function);Brain;Breast;Carbon;Cell Fractionation;Cells;Chickens;Citric Acid Cycle;Colon;Cytoplasm;Data;Development;Enzymes;Epithelial Cells;Exons;Family;Freezing;Fructose;Gel;Genes;Genomics;Glucose;Glycolysis;Glycolysis Inhibition;Growth;Heart;Human;Hypoxia;Immunohistochemistry;In Situ;In Situ Nick-End Labeling;In Vitro;Investigation;Isoenzymes;Knockout Mice;Label;Lactic acid;Lamins;Large T Antigen;Liver;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Mammary Neoplasms;Mammary gland;Measures;Messenger RNA;Metabolic;Metabolism;Mitochondria;Modeling;Mortality Vital Statistics;Mus;Mutation;NADH;Normal tissue morphology;Nude Mice;Oncogenic;Open Reading Frames;Organ;Ovary;Oxygen;Oxygen Consumption;Pathway interactions;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Placenta;Positron-Emission Tomography;Production;Promotor (Genetics);Protein p53;Proteins;Regulation;Relative (related person);Reporting;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Role;Screening procedure;Site;Skeletal muscle structure;Small Interfering RNA;Source;Specimen;Subfamily lentivirinae;TP53 gene;Tamoxifen;Telomerase;Testing;Testis;Tissues;Transgenes;Tumor Tissue;Vascularization;Western Blotting;base;cancer cell;cancer type;cell transformation;cellular transduction;design;glucose metabolism;glucose uptake;in vivo;inhibitor/antagonist;mRNA Expression;neoplastic;neoplastic cell;neurotensin mimic 1;novel;overexpression;protein expression;public health relevance;recombinase;shunt pathway;small hairpin RNA;small molecule;tumor;tumor growth;vector

public_health_relevance:
We anticipate that shRNA silencing or genomic deletion of the PFKFB4 isozyme will attenuate theneoplastic potential of transformed epithelial cells and conversely that increased F26BP (from overexpressionof PFKFB4) will enhance glycolytic flux and augment tumor growth. These findings may validate PFKFB4 as anew target for the inhibition of glycolysis. Accordingly suppression of glycolytic flux in cancer via thedevelopment of small molecule inhibitors of PFKFB4 through computational screening for competitive inhibitorsof the PFKFB4 substrate-binding domain may reduce the high mortality that is associated with cancer.


application_id: 7890505
project_number: 5R01AG027297-05
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2010-06-24
application_type: 5
activity_code: R01
ic: AG
serial_number: 027297
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2006-09-01
project_end_date: 2012-03-31
study_section: Neurodegeneration and Biology of Glia Study Section[NDBG]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating and irreversible neurological disease that progressively alters personality and behavior and destroys cognitive function. With an annual price tag exceeding 100 billion dollars AD is also one of the nation's most costly diseases. In recent years anti-inflammatory agents have emerged as promising compounds for delaying the onset of AD symptoms. Yet our understanding of the mechanisms underlying neuro-immune/inflammatory (im/inf) signaling in the brain remains incomplete. The Ca2+/calmodulin dependent protein phosphatase calcineurin plays a critical role in im/inf signaling cascades in lymphocytes and other cell types but has received little consideration for a similar role in nervous tissue. In the past year we found that calcineurin activation in neuron-glia co-cultures was sufficient for recapitulating several components of the im/inf response found consistently with aging and AD including astrocyte activation and the induction of numerous im/inf-related gene cascades. We also observed a marked and selective upregulation of calcineurin in activated astrocytes surrounding amyloid deposits in AD model mice. The long-term goal of this project is to therefore test the hypothesis that calcineurin is a critical component for the activation of im/inf signaling processes associated with AD. The first two aims will test whether activation of calcineurin and/or the calcineurin-dependent transcription factor NFAT is necessary for im/inf signaling in astrocytes. Biologically relevant inflammatory mediators will be delivered to astrocyte- specific cultures in the presence or absence of potent calcineurin and NFAT inhibitors. The induction of im/inf markers will be assessed with Western blots RT-PCR and cytokine arrays. Potential Ca2+ sources for calcineurin activation in astrocytes will also be examined along with the possibility that calcineurin amplifies its own activity by up-regulating these Ca2+ sources. Aim three will use cell fractionation immunoprecipitation Western blot phosphatase activity assays immunohistochemistry and in situ hybridization to qualitatively and quantitatively assess changes in calcineurin signaling in AD brain specimens and/or in a rodent model of AD. Completion of these studies will greatly increase our knowledge of the role of calcineurin in neuroinflammation and AD and may lead to the development of novel treatment strategies for this disease and other degenerative conditions where neuroinflammation is prominent.

project_terms:
APP gene;Address;Adenoviruses;Age;Age-Months;Aging;Aging-Related Process;Alzheimer's Disease;Alzheimer's disease model;Amygdaloid structure;Amyloid;Amyloidosis;Animal Model;Animals;Anti-Inflammatory Agents;Antibodies;Astrocytes;Behavior;Behavioral;Biological;Biological Assay;Brain;Brain Injuries;Calcineurin;Calmodulin;Catalytic Domain;Cell Fractionation;Cell membrane;Cells;Cerebellum;Chimeric Proteins;Clinical Data;Coculture Techniques;Cognitive;Coupled;Cytosol;Degenerative Disorder;Deposition;Development;Disease;Gene Expression;Genes;Genotype;Glial Fibrillary Acidic Protein;Goals;Hippocampus (Brain);Human;Immune;Immunohistochemistry;Immunoprecipitation;Impaired cognition;In Situ Hybridization;Inferior;Inflammation Mediators;Inflammatory;Inflammatory Response;Kentucky;Knowledge;Lead;Link;Luciferases;Lymphocyte;Measures;Membrane Proteins;Microscopy;Modeling;Molecular;Mus;Mutation;NFAT Pathway;Nerve Degeneration;Nerve Tissue;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Neurons;Nuclear;Nuclear Translocation;Parietal Lobe;Pathologic;Patients;Pattern;Personality;Phosphoric Monoester Hydrolases;Phosphorylation;Play;Price;Process;Property;Protein Isoforms;Protein phosphatase;Rattus;Recruitment Activity;Reporter;Reporting;Research;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Rodent Model;Role;Senile Plaques;Signal Pathway;Signal Transduction;Signaling Molecule;Source;Specimen;Staging;Staining method;Stains;Subcellular Fractions;Swimming;Symptoms;System;T-Lymphocyte;Techniques;Testing;Tissues;Universities;Up-Regulation (Physiology);Ursidae Family;Voltage-Clamp Technics;Western Blotting;Work;age related;aging brain;amyloid pathology;behavior measurement;brain tissue;cell type;cognitive function;computerized data processing;cytokine;human tissue;inflammatory marker;inhibitor/antagonist;insight;interest;molecular marker;mouse model;nervous system disorder;neuroinflammation;neuropsychological;normal aging;novel;nuclear factors of activated T-cells;overexpression;presenilin-1;programs;protein expression;research study;tau Proteins;time use;transcription factor;treatment strategy;voltage


application_id: 7890398
project_number: 5R01CA139844-03
project_title: The role of MRP1 in Protection of Cardiac Injury
administering_ic: NCI
award_notice_date: 2010-07-19
application_type: 5
activity_code: R01
ic: CA
serial_number: 139844
program_official: FORRY, SUZANNE L
project_start_date: 2008-09-25
project_end_date: 2013-07-31
study_section: ZCA1-RPRB-O(J1)
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-08-01
project_abstract:
SPACE PROVIDED. ' The goal of the present application is to characterize the role of multidrug resistance protein 1 (Mrp1) inprotecting the heart from oxidative stress. We postulate that cancer treatment with Adriamycin (ADR)leadsto oxidative stress which in turn leads to production of tumor necrosis factor-a (TNF) that amplifies oxidativestress and causes normal tissue injury. Mrp1 is an ATP-binding cassette (ABC) transporter that mediates theATP-dependent efflux of glutathione (GSH) and its conjugates including the GSH conjugate of the cytotoxicproduct of oxidative stress 4-hydroxynonenal (HNE; GS-HNE). We will test the hypotheses that 1) Cardiacexpression of Mrp1 protects the heart from oxidative stress and injury induced by ADR by mediating efflux ofGS-HNE; 2) Mrp1 expression increases and is localized in plasma membrane and mitochondria in responseto oxidative stress and/or TNF and 3) excessive production of HNE and GS-HNE inactivates Mrp1overwhelming its protective role and exacerbating oxidative injury. Four Specific Aims will test thesehypotheses; Aim 1will utilize Mrp1 null mice to assess its role in protecting the heart from ADR-inducedoxidative stress and injury the ability of MnSODto compensate for loss of Mrp1 and the function of TNF inregulating Mrp1 expression. Aim 2 will characterize the subcellular localization and function of Mrp1 followingADR and TNF treatment. Aim 3 will assessthe role of oxidative stress in the regulation of Mrp1 expressionand localization. Finally Aim 4 will characterize the ability of HNEand GS-HNE to inactivate Mrp1 byalkylation of key cysteine histidine or lysine residues. We will utilize mice of various genotypes (Mrp1 nullmice MnSOD transgenic and heterozygous (+/-) mice) to assessthe roles of these genes in protectionagainst cardiac injury confocal immunofluorescent immunohistochemistry and quantitative immunogoldanalysis for localization of Mrp1 expression in the cardiomyocyte and HEK293 cells for expression of Mrp1to characterize its function; proteomic analyses will be used to identify potential structural isoforms of Mrp1and the sites of HNE alkylation of Mrp1. Understanding the roles of Mrp1 TNF and GSH in protecting theheart from ADR-induced tissue injury will lead to the development of ancillary therapeutic modalities toprotect against such injury and thus permit utilization of higher doses of this highly effectivechemotherapeutic agent.

project_terms:
4 hydroxynonenal;ABCC1 gene;ATP-Binding Cassette Transporters;Adriamycin PFS;Alkylation;Antibodies;Biochemical;Biological Assay;Buthionine Sulfoximine;Cardiac;Cardiac Myocytes;Cardiotoxicity;Cell Line;Cell membrane;Cells;Collaborations;Coupled;Cysteine;Development;Dose;Esters;Fractionation;Genes;Genotype;Glutathione;Goals;Heart;Histidine;Human;Immunohistochemistry;In Vitro;Injury;Knockout Mice;Lead;Lysine;Measures;Mediating;Messenger RNA;Mitochondria;Modality;Morphology;Mus;Normal tissue morphology;Oxidation-Reduction;Oxidative Stress;P-Glycoprotein;P-Glycoproteins;Production;Protein Isoforms;Proteins;Proteomics;Quantitative Microscopy;Regulation;Role;Sarcolemma;Schiff Bases;Site;Testing;Therapeutic;Time;Tissues;Toxic effect;Transgenic Mice;Transgenic Organisms;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Vesicle;Wild Type Mouse;adduct;base;cancer therapy;chemotherapeutic agent;cytotoxic;functional group;in vivo;novel;overexpression;oxidant stress;oxidative damage;response;treatment effect;uptake


application_id: 7890396
project_number: 5R01NS062993-02
project_title: Cyclophilin D as a Therapeutic Target following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2010-06-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 062993
program_official: HICKS, RAMONA R
project_start_date: 2009-07-15
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-T(03)M]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: SULLIVAN, PATRICK G
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 goal of this research is to minimize the secondary cell death and resultant morbidity following traumatic brain injury (TBI). Clinical interventions to improve outcome following TBI are extremely limited. Mitochondrial dysfunction is a pivotal link in the neuropathological sequalae of traumatic brain injury (TBI). TBI-induced increases in mitochondrial Ca2+ cycling/overload ultimately lead to opening of the mitochondrial permeability transition pore (mPTP). This pore located on the inner mitochondrial membrane opens in response to elevated Ca2+ and oxidative stress and is gated by the mitochondrial protein cyclophilin D (CypD). When prolonged mPTP opening is catastrophic as a result of the loss of mitochondrial membrane potential and the release of calcium and death-related proteins from mitochondria. The goal of this research is to minimize the secondary cell death and resultant morbidity following TBI by limiting mPTP opening. The immunosuppressant Cyclosporin A (CsA) inhibits mPTP opening by binding to CypD. We and others previously demonstrated that CsA reduces the extent of tissue damage when administered following experimental TBI. Unfortunately CsA is toxic at high concentrations resulting from its inhibition of calcineurin. Recently we have demonstrated that CypD levels in primary neurons are approximately double the levels found in astrocytes and that CypD levels are also significantly higher in synaptic mitochondria (neuronal origin) compared to non-synaptic mitochondria (predominately non-neuronal origin). As a result of their high CypD content we hypothesize that neuronal mitochondria are more vulnerable to mPTP opening and also require greater CsA levels to inhibit mPTP opening. To test this hypothesis we propose to use genetic and newer pharmacologic approaches to inhibit CypD following neuronal injury. Specifically we will use CypD knockout mice and a CsA derivative NIM811 which does not bind to or inhibit calcineurin. The specific aims are: 1: To evaluate the hypothesis that the high CypD content of neuronal mitochondria enhances vulnerability to mPTP opening following insults that result in elevated intracellular Ca2+ and oxidative stress. 2: To evaluate the hypothesis that the levels of the CypD inhibitor NIM811 required to protect neurons from excitotoxic insult is proportional to their CypD content. 3: To examine the hypothesis that mitochondrial CypD levels modulate the neuropathologic and functional outcome following TBI in mice. 4: To examine the hypothesis that CypD inhibitor NIM811 reduces tissue damage and improves functional outcome following TBI. Based on the results of these studies we anticipate that NIM811 will exhibit strong potential as novel therapy for TBI. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a devastating healthcare problem in the United States with no pharmacological treatments currently approved for clinical intervention following injury. Improved TBI treatment options are urgently needed. This proposal examines the potential of NIM811 a derivative of CsA to limit the brain damage and dysfunction resulting from TBI.

project_terms:
Abbreviations;Adenine Nucleotide Translocase;Adenine Nucleotides;Affinity;Amino Acids;Animal Model;Astrocytes;Attenuated;Binding (Molecular Function);Binding Proteins;Blood - brain barrier anatomy;Brain Injuries;Calcineurin;Calcium;Calpain;Cell Death;Cessation of life;Chemical Structure;Cleaved cell;Clinical;Clinical Trials;Cyclophilin A;Cyclophilins;Cyclosporine;Cyclosporins;Cytosol;Dose;Endoplasmic Reticulum;Event;Exhibits;Figs - dietary;Functional disorder;Generic Drugs;Genes;Genetic;Goals;Healthcare;Heterozygote;Hydrogen Peroxide;Immunosuppressive Agents;In Vitro;Injury;Inner mitochondrial membrane;Intervention;Isoleucine;Knockout Mice;Lead;Link;Liver Mitochondria;Membrane Potentials;Mitochondria;Mitochondrial Matrix;Mitochondrial Proteins;Mitochondrial Swelling;Modeling;Morbidity - disease rate;Mus;N-Methylaspartate;Names;Neuroglia;Neuronal Injury;Neurons;Nomenclature;Outcome;Oxidative Stress;Peptidylprolyl Isomerase;Performance;Permeability;Pharmaceutical Preparations;Pharmacological Treatment;Proteins;Rattus;Reactive Oxygen Species;Research;Specificity;Staging;Synapses;Synaptosomes;Testing;Tissues;Toxic effect;Traumatic Brain Injury;United States;Wallerian Degeneration;analog;apoptosis inducing factor;base;calcium green;caspase;cis-trans-Isomerases;controlled cortical impact;cyclophilin D;endonuclease G;functional outcomes;improved;in vivo;inhibitor/antagonist;leucine methyl ester;mitochondrial dysfunction;mitochondrial membrane;mitochondrial permeability transition pore;neuron loss;novel;public health relevance;response;solute;therapeutic target

public_health_relevance:
Traumatic brain injury (TBI) is a devastating healthcare problem in the United States with no pharmacologicaltreatments currently approved for clinical intervention following injury. Improved TBI treatment options areurgently needed. This proposal examines the potential of NIM811 a derivative of CsA to limit the braindamage and dysfunction resulting from TBI.


application_id: 7889065
project_number: 2R01DK048498-16
project_title: Surgical Studies of Functional Gene Expression
administering_ic: NIDDK
award_notice_date: 2010-05-19
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2014-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The mammalian intestinal mucosa is in a constant state of renewal that is characterized by active proliferation of stem cells localized in the crypts progression of these cells up the crypt villus axis with cessation of proliferation and subsequent differentiation. A delicate and precise balance of proliferation -> differentiation -> apoptosis must exist in the gut mucosa to maintain this normal intestinal homeostasis. Surgical resection of the small intestine results in an adaptive hyperplasia whereas the inability to provide enteral nutrients as occurs in certain post-operative or trauma patients results in atrophy. The major focus of our group has been the analysis of mechanisms regulating intestinal proliferation differentiation adaptation and apoptosis. With the support of this grant we have made great strides in our better understanding of the molecular mechanisms regulating intestinal homeostasis. We have shown that stimulation of PI3K/Akt increases normal intestinal proliferation. Our most recent findings have identified novel and differential roles for the mammalian target of rapamycin (mTOR) protein complex a major downstream effector of PI3K in intestinal proliferation and differentiation and intestinal cell survival. In preliminary findings we have shown that inhibition of mTORC2 but not mTORC1 enhances intestinal cell differentiation suggesting differential effects for these proteins in the gut. Also we have recently described the molecular mechanisms contributing to glutamine-mediated intestinal cell survival and proliferation; the PI3K/mTOR pathway plays an important protective role to limit apoptosis associated with cellular stress. Finally we have demonstrated a novel role for the mTOR pathway in intestinal cell autophagy following glutamine deprivation. Based on our recent published and preliminary findings we have refined our central hypothesis to state that intestinal cell proliferation and differentiation are regulated by signaling mechanisms involving the PI3K/mTOR pathway acting on critical downstream effector proteins; novel and differential effects of mTOR and Akt components exist that further add to the complex but highly regimented regulation of intestinal homeostasis. To examine this hypothesis we have planned experiments with the following Specific Aims: 1) to determine the differential effects of mTOR complexes on intestinal cell homeostasis 2) to delineate the signaling proteins that mediate the effects of mTOR in the intestine and 3) to define the role of mTOR/mTOR complexes in intestinal cell growth in vivo. The studies in the current proposal represent direct extensions of our previous findings and are designed to define in a systematic fashion the molecular mechanisms and signaling events regulating the processes of intestinal proliferation differentiation and adaptation. To achieve our goals we have assembled a multidisciplinary diverse and highly collaborative team of investigators who each bring unique expertise and background to the project.  
  
PUBLIC HEALTH RELEVANCE: The intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to this critical function are poorly understood. Our recent findings have identified novel roles for components of the PI3K/Akt/mTOR signaling pathway in intestinal homeostasis. Delineating the cellular factors and signaling pathways regulating these processes is crucial to our understanding of not only normal gut development and maturation but also the effects of surgical resection and stress on intestinal adaptation and survival.

project_terms:
1-Phosphatidylinositol 3-Kinase;Alkaline Phosphatase;Apoptosis;Atrophic;Autophagocytosis;Brush Border;Cell Differentiation process;Cell Proliferation;Cell Survival;Cell physiology;Cells;Cellular Stress;Characteristics;Chemicals;Complex;Cyclin-Dependent Kinase Inhibitor;Development;Differentiated Gene;Enteral;Enterocytes;Enteroendocrine Cell;Enzymes;Epithelial Cells;Equilibrium;Event;Excision;Gene Expression;Glutamine;Glycogen Synthase Kinase 3;Goals;Goblet Cells;Grant;Growth;Homeostasis;Hyperplasia;Intestinal Mucosa;Intestinal Volvulus;Intestines;Ischemia;MAPK8 gene;Mediating;Molecular;Mucous Membrane;Nutrient;Oligo-16-Glucosidase;Operative Surgical Procedures;PTEN gene;Paneth Cells;Pathway interactions;Patients;Pattern;Play;Postoperative Period;Process;Proliferating;Proteins;Publishing;Regulation;Research Personnel;Role;Signal Pathway;Signal Transduction;Signaling Protein;Sirolimus;Small Intestines;Stem cells;Stress;Sucrase;Trauma;Tumor Suppressor Proteins;Villus;base;cell growth;cell type;deprivation;design;in vivo;inhibitor/antagonist;mTOR protein;multidisciplinary;novel;overexpression;protein complex;public health relevance;research study


application_id: 7888164
project_number: 5R01NS037717-10
project_title: Transcriptional control of oligodendrocyte differentiation and myelination
administering_ic: NINDS
award_notice_date: 2010-07-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 037717
program_official: UTZ, URSULA
project_start_date: 2000-03-01
project_end_date: 2014-05-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1906514
contact_pi: QIU, MENGSHENG
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): Oligodendrocytes are myelinating glial cells found in all regions of the central nervous system. The major function of oligodendrocytes is to form myelin sheaths around axons to ensure the rapid and faithful transmission of electrical signals. During development oligodendrocytes precursor cells (OPCs) have to go through a series of morphological and molecular changes before they become fully differentiated into mature myelinating oligodendrocytes. The differentiation and myelination processes of oligodendrocytes are tightly controlled by transcription factors. Recent studies have demonstrated that Sox10 transcription factor directly stimulates OPC differentiation and myelin gene expression. However OPC differentiation is tightly regulated by other transcription factors (TFs) including Nkx2.2 Olig1 Hes5 and Id4 all of which are expressed in undifferentiated OPC cells in the developing central nervous system. While Nkx2.2 and Olig1 function to promote OPC differentiation Hes5 and Id4 act as inhibitors of OPC maturation. The functional relationship of these four regulatory TFs in the control of OL differentiation has not been determined. In this application we hypothesize that Nkx2.2 enhances OPC maturation indirectly by suppressing the expression or function of Hes5 and Id4 but functions synergistically with Olig1 in promoting OPC differentiation. These hypotheses will be tested in the first two aims of the proposal. Recent data showed that Nkx2.2 is rapidly down-regulated in differentiated OLs and over-expression of Nkx2.2 in oligodendrocyte cell line inhibits MBP gene expression raising the possibility that Nkx2.2 switches its role to become a repressor of myelin gene expression in mature OLs to prevent excessive myelin production. This possibility will be examined in the third aim of the proposal. Finally we will test the hypothesis that persistent expression of Sox10 in mature OLs functions to maintain myelin gene expression and myelin sheath stability. The interplay of Sox10 and Nkx2.2 in myelinating OL cells may be responsible for the delicate balance of myelin production and structural maintenance. This line of study could help us understand molecular pathways that control axonal myelination process and provide insights into the development of molecular approaches to stimulate oligodendrocyte regeneration and remyelination in demyelinating diseases. PUBLIC HEALTH RELEVANCE: The proposed studies will provide important information on the function and regulations of transcription factors that control oligodendrocyte differentiation and myelin gene expression in the developing central nervous system. Knowledge obtained from this study can help us understand the molecular pathways that govern the differentiation and myelination of oligodendrocytes and provide cues for promoting oligodendrocyte regeneration and axonal remyelination in neurological patients and spinal cord injury patients.

project_terms:
Axon;Binding (Molecular Function);Cell Differentiation process;Cell Line;Cell Maturation;Cells;Chickens;Cues;Data;Demyelinating Diseases;Development;Embryo;Ensure;Equilibrium;Gene Expression;Genes;Genetic;Knowledge;Maintenance;Molecular;Mutation;Myelin;Myelin Sheath;Natural regeneration;Neuraxis;Neuroglia;Neurologic;Nkx-2.2 protein;Oligodendroglia;Pathway interactions;Patients;Principal Investigator;Process;Production;Promotor (Genetics);Proteins;Regulation;Role;Series;Signal Transduction;Spinal Cord;Spinal cord injury patients;Testing;Transcriptional Regulation;Transgenic Animals;Undifferentiated;axon regeneration;inhibitor/antagonist;insight;mutant;myelination;oligodendrocyte precursor;precursor cell;premature;prevent;programs;public health relevance;transcription factor;transmission process


application_id: 7887647
project_number: 1R01CA128903-01A2
project_title: Chemical Probes of Immunoproteasome Function in Cancer
administering_ic: NCI
award_notice_date: 2010-06-07
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: CA
serial_number: 128903
suffix: A2
program_official: LEES, ROBERT G
project_start_date: 2010-06-07
project_end_date: 2015-04-30
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 8152159
contact_pi: KIM, KYUNG BO
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
project_abstract:
DESCRIPTION (provided by applicant): The essential roles of the ubiquitin-proteasome system (UPS) in many cellular processes are now well recognized. However many questions still remain unanswered. Intriguing yet not fully understood are the functions of the immunoproteasome an alternative form of the constitutive proteasome. It has been shown that the roles of the immunoproteasome in cells are not just limited to the generation of antigenic peptides but far more multifaceted. In this regard recent studies have shown that catalytic subunits of the immunoproteasome are implicated in various types of diseases including cancer. Despite these therapeutic implications the immunoproteasome remains largely untapped for cancer drug discovery. A better understanding of immunoproteasome functions would be crucial in developing the optimum LMP2 inhibitor(s). In our continuing efforts to better understand the role of the immunoproteasome in cells we have recently developed a small molecule probe ('UK-101') that specifically targets LMP2 a major catalytic subunit of the immunoproteasome. Further we found that LMP2 is highly expressed in several types of primary tumor tissues and cancer cell lines. Interestingly cancer cells that highly express LMP2 are markedly more sensitive to UK-101 than those expressing low level of LMP2. Consistent with these in vitro results UK-101 inhibits tumor growth in a mouse xenograft model of human prostate tumor that highly expresses LMP2 but not that of tumor that expresses low level of LMP2. These observations further support a potential role of LMP2 in cancer cell growth and survival. The goals of this application are to determine the roles of the immunoproteasome in prostate cancer and to investigate therapeutic potentials of the immunoproteasome-targeting approaches in cancer therapy. Towards this goal we propose to use innovative chemical probes that selectively target and visualize individual catalytic subunits of the immunoproteasome. In order to accomplish this goal four specific aims are proposed: 1) To validate the immunoproteasome as the major pharmacological target of UK-101 2) To determine dynamic cellular distribution of the catalytically active immunoproteasome and 3) To determine the unique functions of the immunoproteasome compared to the constitutive proteasome and 4) To develop an optimum LMP2 inhibitor(s) by generating a structurally diversified small molecule library. The proposed work integrates both chemical and biological approaches. Successful completion of the project will significantly expand our knowledge on the role of the immunoproteasome. In addition the study will yield critical information in developing immunoproteasome-specific inhibitors as a potential therapeutic agent. Finally small molecule probes that will be used in this application will provide valuable research tools for the ubiquitin-proteasome biology community.   
  
PUBLIC HEALTH RELEVANCE: Small molecule probes are valuable tools in deciphering protein functions. We have developed a novel cell permeable small molecule that selectively targets the immunoproteasome. Using this small molecule and other molecular tools we will investigate the roles of the immunoproteasome in cancer cells and therapeutic potentials of the immunoproteasome-targeting approaches in cancer therapy.

project_terms:
Affinity;Antineoplastic Agents;Attention;Binding Proteins;Biological;Biology;Bortezomib;Cancer Cell Growth;Cancer cell line;Catalytic Domain;Cell Death;Cell Line;Cell physiology;Cells;Chemicals;Clinical;Communities;Complex;Data;Development;Disease;Dominant-Negative Mutation;Down-Regulation;Generations;Goals;Human;In Vitro;Individual;Inflammatory;Inflammatory Bowel Diseases;Interferon Type II;Investigation;Knowledge;Libraries;Malignant Neoplasms;Malignant neoplasm of prostate;Molecular;Multiple Myeloma;Mus;Normal Cell;Organ;Peptide Library;Peptides;Pharmaceutical Preparations;Play;Primary Neoplasm;Prostatic Neoplasms;Proteasome Inhibitor;Proteomics;Publications;Refractory;Research;Role;Screening procedure;Signal Pathway;Small Interfering RNA;Solid Neoplasm;System;Therapeutic;Therapeutic Agents;Toxic effect;Tumor Tissue;Ubiquitin;Up-Regulation (Physiology);Work;Xenograft Model;cancer cell;cancer therapy;drug discovery;imaging probe;in vivo;inhibitor/antagonist;innovation;multicatalytic endopeptidase complex;neoplastic cell;novel;overexpression;protein function;public health relevance;small molecule;small molecule libraries;tool;tumor;tumor growth

public_health_relevance:
Project Narrative:Small molecule probes are valuable tools in deciphering protein functions. We havedeveloped a novel cell permeable small molecule that selectively targets theimmunoproteasome. Using this small molecule and other molecular tools we willinvestigate the roles of the immunoproteasome in cancer cells and therapeutic potentialsof the immunoproteasome-targeting approaches in cancer therapy.


application_id: 7887235
project_number: 2R01AI048850-07
project_title: Fatty Acid Binding Proteins in Macrophage Function
administering_ic: NIAID
award_notice_date: 2010-04-21
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: AI
serial_number: 048850
program_official: PEYMAN, JOHN A
project_start_date: 2003-04-01
project_end_date: 2014-04-30
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1882106
contact_pi: SUTTLES, JILL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Fatty acid binding proteins FABPs have been identified as central regulators of both metabolic and inflammatory pathways.  FABPs act as intracellular receptors for a variety of hydrophobic compounds enabling their diffusion within the cytoplasmic compartment.  We have shown that adipocyte FABP (A-FABP) and epithelial FABP (E-FABP) regulate macrophage cholesterol trafficking and inflammatory function in part via regulation of the activity of the peroxisome proliferator-activated receptor (PPAR-?).  Macrophages and dendritic cells (DC) from FABP- deficient mice are defective in expression of proinflammatory cytokines and are inefficient in the promotion of proinflammatory T cells responses during antigen presentation.  FABP-deficient mice are protected from development of experimental autoimmune encephalomyelitis (EAE). Overall the results of our research suggest that FABPs regulate a molecular switch between metabolic and inflammatory pathways in macrophages and DC and as a consequence regulate both innate and adaptive immune responses.  We will continue our studies of these proteins through the pursuit of the following specific aims: Specific Aim 1 is to identify the molecular mechanism(s) by which FABPs affect inflammatory cytokine gene expression in macrophages and DC.  We have found that FABP-deficiency is accompanied by elevated activity of AMP- activated protein kinase (AMPK) and that AMPK is a negative regulator of macrophage inflammatory function.  Experiments will be performed to determine the link between FABPs AMPK and PPAR-? testing the hypothesis that FABP regulation of energy stores regulates AMPK activity which in turn modulates inflammatory activity.  Specific Aim 2 is to further delineate the impact of FABP-deficiency on autoimmune disease using EAE as a model.  This aim will include an evaluation of the specific contributions of T cell priming and of the tissue environment towards the protection from EAE displayed by FABP-deficient mice.  In this aim we will also test the in vivo efficacy of inhibitors of FABPs as an anti-inflammatory therapy using the EAE model.  Specific Aim 3 is to test the hypothesis that the expression of FABPs links dietary fat intake with exacerbated inflammatory disease. We will evaluate the effects of fat intake on FABP expression in leukocyte populations and the association of diet-induced FABP expression with inflammatory responsiveness.  The completion of these studies will provide a more comprehensive understanding of how FABPs regulate immune and inflammatory responses.  
  
PUBLIC HEALTH RELEVANCE:  Fatty acid-binding proteins (FABPs) have been shown to play a role in obesity and Type 2 diabetes.  This proposal is based on studies demonstrating that FABPs also strongly promote inflammation and contribute to autoimmune inflammatory disease.  The goals of the project are to determine the mechanisms by which FABPs regulate inflammatory function in leukocytes and to test the hypothesis that FABPs constitute an accessible and effective target for treatment of inflammatory disease.  Given the recent identification of small molecule inhibitors of FABP function this project has direct relevance to human health.

project_terms:
5'-AMP-activated protein kinase;Adipocytes;Adipose tissue;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antigen Presentation;Autoimmune Diseases;Autoimmune Process;Automobile Driving;Brain;Cells;Chronic;Cytokine Gene;Data;Dendritic Cells;Development;Diet;Dietary Fats;Diffusion;Disease;Encephalomyelitis;Environment;Epithelial;Evaluation;Exhibits;Experimental Autoimmune Encephalomyelitis;Fatty acid glycerol esters;Gene Expression;Genes;Glycogen Synthase Kinases;Goals;Health;Human;Hydroxymethylglutaryl-CoA reductase;Immune;Immune response;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Intake;Interferons;Interleukin-17;Leukocytes;Link;Lipids;Metabolic;Modeling;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nuclear;Obesity;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Play;Population;Production;Protein Deficiency;Proteins;Regulation;Research;Role;Spinal Cord;T cell response;T-Lymphocyte;Testing;Tissues;Transcriptional Activation;Wild Type Mouse;Work;base;cholesterol trafficking;cytokine;disorder risk;fatty acid-binding proteins;feeding;in vivo;inhibitor/antagonist;mTOR protein;macrophage;protein expression;protein function;public health relevance;receptor;research study;response;small molecule;transcription factor


application_id: 7886826
project_number: 5R01CA125166-03
project_title: Transcriptional Repression of Sodium-Iodide Symporter in Thyroid Carcinoma
administering_ic: NCI
award_notice_date: 2010-06-11
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 125166
program_official: OKANO, PAUL
project_start_date: 2008-07-01
project_end_date: 2012-06-30
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 7875253
contact_pi: AIN, KENNETH BRUCE
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): Distantly metastatic dedifferentiated thyroid cancer is a fatal disease without effective treatment. This is from loss of ability to concentrate iodide rendering it unresponsive to radioactive iodine the only known systemic therapy. Iodide uptake requires expression of sodium-iodide symporter (hNIS). Hypermethylation of hNIS promoter region was thought to be a likely mechanism for loss of hNIS expression in thyroid cancer cells. hNIS expression and function is restored after treating these cells with demethylating and histone deacetylase-inhibiting agents. It was presumed that these agents permit transcriptional machinery access to the gene by relaxing chromatin compaction. 5-azacytidine (AzaC; DNA methyltransferase inhibitor) and sodium butyrate (NaB; putative histone deacetylase inhibitor) both singly and together restore hNIS expression and function to thyroid cancer cell lines. To show relaxed hNIS chromatin structures suggested by their presumed epigenetic effects we assessed DNAse I digestion rate of genomic hNIS regions when AzaC and NaB restored hNIS mRNA expression and hNIS function. Surprisingly these treatments did not produce enhanced DNAse I sensitivity suggesting the absence of effect on chromatin compaction. NaB-treated dedifferentiated thyroid cancer cells transfected with a luciferase reporter construct containing hNIS gene promoter stimulated both luciferase expression and native hNIS expression. Treating these cells with protein synthesis inhibitors (PSIs; cycloheximide anisomycin emetine) stimulated luciferase expression in a dose-dependent time course-dependent cell type-specific and promoter-specific fashion; as well as restored endogenous hNIS gene mRNA expression. This suggested presence of a trans-acting transcriptional inhibitor NIS-repressor responsible for loss of hNIS expression. We mapped the hNIS promoter sequence region responsible for this effect the NIS-repressor binding site (NRBS). NRBS used as a radiolabeled probe in electrophoretic mobility shift assays with thyroid cancer cell nuclear extract shows sequence-specific protein binding. These proteins were analyzed with liquid chromatography coupled to tandem mass spectrometry and revealed identity of a significant component of NIS-repressor. We hypothesize that loss of iodide transport activity in thyroid cancer results from loss of hNIS gene expression consequent to NIS-repressor binding to the hNIS promoter. This novel mechanism may underlie or be in addition to presumed epigenetic mechanisms of hNIS gene reactivation reported with various pharmacologic agents. Treatments directed to reduce or antagonize NIS- repressor components should restore hNIS gene expression responsible for iodide transport enabling I-131 therapy of dedifferentiated thyroid cancers. Our aims are to confirm our identification of NIS-repressor protein and identify other protein complex components discern its physiological and pathophysiological effects and develop strategies targeting it. This should result in treatments to restore NIS activity in dedifferentiated thyroid cancers restoring use of radioactive iodine to treat thyroid cancer metastases.  
  
Public Health Relevance Statement: Thyroid cancer for unknown reasons is the most rapidly increasing cancer in the United States in both men and women and it is the most common cancer in white women between 20 and 30 years of age. Although 75% of thyroid cancer patients respond adequately to radioactive iodine therapy 10% of patients lose response to this treatment and eventually die from disseminated tumor. Development of new methods of restoring clinical response to radioactive iodine could save lives.

project_terms:
ADP Ribose Transferases;Accounting;Affinity Chromatography;Age-Years;Anisomycin;Aortic Aneurysm;Azacitidine;Binding (Molecular Function);Binding Proteins;Binding Sites;Biological Assay;Butyrates;C-terminal;CREB1 gene;Calcium;Calmodulin;Cancer Patient;Cancer cell line;Catalytic Domain;Cattle;Cell Line;Cells;Chromatin;Chromatin Structure;Chromosomes;Clinical;Clinical Trials;Co-Immunoprecipitations;Complementary DNA;Complex;Consensus;Coupled;CpG Islands;Cross-Linking Reagents;Cycloheximide;DNA Binding;DNA Binding Domain;DNA Methylation;DNA Methyltransferase Inhibitor;DNA Repair;DNA ligase III;Data;Deoxyribonuclease I;Depsipeptides;Development;Digestion;Disease;Distal;Distant;Dominant-Negative Mutation;Dose;Drug usage;Effectiveness;Egtazic Acid;Electrophoretic Mobility Shift Assay;Elements;Emetine;Enhancers;Epigenetic Process;Fractionation;Functional disorder;Gel;Gel Chromatography;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genomics;Globulins;Goals;Grant;Histone Deacetylase;Histone Deacetylase Inhibitor;Human;Hypermethylation;I131 isotope;Immunoglobulin G;Immunohistochemistry;In Vitro;Incubated;Iodides;Iodine;Isotopically-Coded Affinity Tagging;Label;Life;Ligands;Light;Liquid Chromatography;Luciferases;Lung;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of thyroid;Maps;Measures;Membrane;Messenger RNA;Methodology;Methods;Molecular Conformation;Molecular Weight;Mus;Neoplasm Metastasis;Nuclear;Nuclear Extract;Nude Mice;Oligonucleotides;Operative Surgical Procedures;Orphan Drugs;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Physiological;Physiology;Plasmids;Poly(ADP-ribose) Polymerases;Precipitation;Probability;Production;Promoter Regions (Genetics);Promotor (Genetics);Protein Binding;Protein Structure Initiative;Protein Synthesis Inhibitors;Proteins;Publishing;Pulmonary Surfactant-Associated Protein B;Pulmonary Surfactant-Associated Proteins;Radiation;Radioactive;Radioactive Iodine;Radiolabeled;Rattus;Reagent;Recombinants;Regulatory Element;Relative (related person);Reporter;Reporting;Repression;Repressor Proteins;Research;Run-On Assays;Running;Site;Small Interfering RNA;Sodium Butyrate;Streptavidin;Systemic Therapy;TEV protease;TNFSF11 gene;Techniques;Testing;Thyroglobulin;Thyroid Gland;Thyroid carcinoma;Thyrotropin;Time;Tissues;Transcription Initiation Site;Transcription factor genes;Transfection;Translations;Treatment Failure;Tretinoin;Trichostatin A;Trypsin;Type I DNA Topoisomerases;United States;Upstream Enhancer;Validation;Valproic Acid;Vorinostat;Weight;Western Blotting;Woman;activating transcription factor;base;cancer cell;cell type;chelation;effective therapy;expectation;functional restoration;gene repression;human tissue;in vivo;inhibitor/antagonist;mRNA Expression;men;mutant;novel;pre-clinical;protein complex;public health relevance;radiotracer;receptor;repaired;research study;response;restoration;sodium-iodide symporter;tandem mass spectrometry;therapeutic target;thyroid transcription factor 1;transcription factor;tumor;tumor xenograft;uptake


application_id: 7886766
project_number: 5R01AG027258-03
project_title: Telomeric dysfunction and the premature aging and cancer-prone disease Werner syn
administering_ic: NIA
award_notice_date: 2010-06-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 027258
program_official: CHATTERJI, MINKI
project_start_date: 2008-08-01
project_end_date: 2012-06-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 7034221
contact_pi: ORREN, DAVID KEITH
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Telomeres are specialized structures on chromosome ends that are essential for genome stability and cellular replicative capacity. Maintenance of proper telomere structure and length allows continued cell division. However most replicating cells in the body do not express the maintenance enzyme telomerase and gradually lose telomeric DNA eventually reaching a critically short telomere length that triggers cellular senescence and/or apoptosis. Theoretically significant accumulation of senescent cells or loss of apoptotic cells in tissues occurs late in life and may underlie development of certain normal aging characteristics. However solid support for the relationship between telomere dysfunction cellular senescence and possible aging phenotypes in normal individuals is currently lacking. The premature aging disease Werner syndrome (WS) that shows early onset and increased frequency of many deleterious aging features (including cancer atherosclerosis osteoporosis cataracts diabetes and hypertension) is caused by loss of function of a single protein WRN. Cells derived from WS patients show telomeric abnormalities and a dramatic premature cellular senescence that is prevented by prior expression of telomerase. Investigations from several laboratories (including ours) indicate that WRN functions in telomere maintenance possibly in coordination with the telomeric protein TRF2. Thus WS is an excellent model for studying the relationships between telomere maintenance cellular senescence apoptosis and development of specific aging characteristics. This proposal will examine the biochemical activities of WRN (in conjunction with TRF2 and other telomeric factors) on relevant telomeric DNA structures and determine its protein partners during its function in telomere metabolism with specific emphasis on telomeric replication. In addition telomere dynamics (replication kinetics and length alterations) and cellular senescence in normal and WS cells will be examined during chronic treatment with selected DNA damaging agents. These studies will clarify the telomeric function of WRN and determine whether persistent DNA lesions in telomeric regions exacerbate telomere loss over time in WS cells compared to normal cells and provide further support to the role of telomere dysfunction in the development of specific age-related characteristics in WS as well as in normal aging. Thus this proposal will implicate and examine basic mechanisms at work in genome maintenance and suppression of certain aging phenotypes as well as cancer. PUBLIC HEALTH RELEVANCE: This proposal examines the role of a specific protein WRN in the maintenance of chromosome ends otherwise known as telomeres. When the function of human WRN is lost (in the hereditary disease Werner syndrome) the resulting telomeric abnormalities trigger cell senescence or cell death and in time cause early development of aging features and cancer in affected individuals. By investigating Werner syndrome and the role of WRN in telomere metabolism this proposal will help understand basic cellular mechanisms that act to suppress development of specific aging characteristics as well as cancer.

project_terms:
Affect;Age;Aging;Apoptosis;Apoptotic;Atherosclerosis;Back;Binding (Molecular Function);Biochemical;Cataract;Cell Aging;Cell Death;Cell division;Cells;Characteristics;Chromosomal Instability;Chromosomes;Chronic;Cisplatin;DNA;DNA Damage;DNA Structure;DNA lesion;Development;Diabetes Mellitus;Disease;Dose;Ensure;Enzymes;Exonuclease;Fibroblasts;Frequencies (time pattern);Functional disorder;Genes;Genetic Recombination;Genome;Genome Stability;Hereditary Disease;Human;Hypertension;Individual;Investigation;Kinetics;Knowledge;Laboratories;Length;Life;Link;Maintenance;Malignant Neoplasms;Mediating;Metabolic;Metabolism;Methods;Modeling;Monitor;Normal Cell;Osteoporosis;Oxidative Stress;Pathway interactions;Patients;Phenotype;Play;Premature aging syndrome;Process;Proteins;Reaction;Research;Resolution;Role;Solid;Structure;Study models;TERF1 gene;Telomerase;Telomere Maintenance;Telomeric Repeat Binding Protein 2;Time;Tissues;Werner Syndrome;Work;age related;early onset;helicase;human WRN protein;loss of function;normal aging;nuclease;premature;prevent;public health relevance;research study;senescence;telomere;tumor progression


application_id: 7886140
project_number: 1R01EY020672-01
project_title: Endogenous Specific Inhibitor of Corneal Lymphangiogenesis
administering_ic: NEI
award_notice_date: 2010-03-22
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: EY
serial_number: 020672
program_official: SHEN, GRACE L
project_start_date: 2010-04-01
project_end_date: 2014-03-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Absence of blood and lymphatic vessels in the normal cornea is essential for optical clarity and optimal vision. Numerous pathological disorders result in corneal neovascularization that is responsible for blindness in hundreds of millions of individuals worldwide. The vascular endothelial growth factor (VEGF) family and their receptors (VEGFR) are critical elements of the tightly regulated balance of endogenous angiogenesis stimulators and inhibitors which when disrupted results in neovascularization. The principal positive regulators of blood (hemangiogenesis) and lymphatic (lymphangiogenesis) in the cornea are VEGF-A and VEGF-C respectively. Among the many inhibitors of hemangiogenesis that reside in the cornea we have shown that soluble VEGFR-1 (sVEGFR-1) by acting as a trap for VEGF-A is essential for corneal avascularity (Ambati et al. Nature 2006). In contrast the molecular basis of the alymphatic cornea has not been resolved; indeed no endogenous specific inhibitor of lymphangiogenesis in any tissue has yet been reported. In new and exciting studies we identified the existence of a novel secreted splice variant of VEGFR-2 in mouse and human (sVEGFR-2) (Albuquerque et al. Nature Medicine 2009). Surprisingly loss of sVEGFR-2 resulted in spontaneous invasion of lymphatic but not blood vessels into the mouse cornea at birth. sVEGFR-2 also specifically inhibited injury-induced corneal lymphangiogenesis and dramatically reduced corneal allograft rejection. This proposal will test the hypothesis that the lymphatic specificity of sVEGFR-2 is due to its existence as a monomer that interacts with and antagonizes VEGF-C but not VEGF-A. The Specific Aims of this proposal are to define the expression and function of sVEGFR-2 during mouse and human corneal development decipher the molecular mechanisms by which mouse and human sVEGFR-2 inhibit lymphangiogenesis but not hemangiogenesis and resolve the spatial and temporal expression and function of sVEGFR-2 in the mouse cornea following injury and allograft rejection. By providing clarifying insights into a critical endogenous regulator of lymphangiogenesis and identifying mechanisms that might serve as potential targets for advancing novel therapies for corneal neovascularization and transplant rejection these studies directly address the 5-year goals of the NEI Corneal Diseases program. The impact of these studies also extends to pathological states such as tumor metastasis lymphedema and lymphangioma which can be better studied and possibly treated by modulating the endogenous uncoupler of lymphatic and blood vessels we have discovered.  
  
PUBLIC HEALTH RELEVANCE: Corneal neovascularization and transplant rejection which involve abnormal blood and lymphatic vessels lead to blindness in millions worldwide. We discovered a naturally occurring molecule (sVEGFR-2) that selectively blocks lymphatic but not blood vessels. By molecularly uncoupling these intertwined processes we introduce a new research tool that can be used to specifically study lymphatic vascular biology and a new target that can lead to novel therapies for corneal blindness.

project_terms:
Accounting;Address;Adult;Allografting;Angiogenesis Inducing Agents;Binding (Molecular Function);Biochemical;Biology;Birth;Blindness;Blood;Blood Vessels;Cell surface;Cornea;Corneal Diseases;Corneal Neovascularization;Data;Dendritic Cells;Development;Disease;Elements;Equilibrium;Extracellular Domain;Family;Family member;Goals;Graft Rejection;Growth;Heterodimerization;Human;Immune;Individual;Inflammatory;Injury;Keratoplasty;Lead;Lymphangiogenesis;Lymphangioma;Lymphatic;Lymphatic Endothelial Cells;Lymphatic vessel;Lymphedema;Mediating;Medicine;Membrane;Modeling;Molecular;Mus;Nature;Neoplasm Metastasis;Optics;Organ;Pathology;Pharmaceutical Preparations;Process;RNA Interference;RNA Splicing;Recombinants;Regulation;Relative (related person);Reporting;Research;Risk;Signal Transduction;Source;Specificity;Surgical sutures;Testing;Tissues;Transplantation;Variant;Vascular Endothelial Growth Factor A;Vascular Endothelial Growth Factor C;Vascular Endothelial Growth Factor D;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factor Receptor-1;Vascular Endothelial Growth Factor Receptor-2;Vascular Endothelial Growth Factor Receptor-3;Vascular Endothelial Growth Factors;Vision;World Health;allograft rejection;angiogenesis;base;cell motility;corneal allograft;high risk;inhibitor/antagonist;insight;lymph nodes;monomer;neovascularization;novel;novel strategies;prevent;programs;public health relevance;receptor;tool;tumor


application_id: 7885559
project_number: 5K02DA019656-05
project_title: Neuropeptidergic Inhibition of Spinal Pain Transmission
administering_ic: NIDA
award_notice_date: 2010-06-18
opportunity_number: PA-00-020
application_type: 5
activity_code: K02
ic: DA
serial_number: 019656
program_official: THOMAS, DAVID A
project_start_date: 2007-07-01
project_end_date: 2012-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The candidate for an Independent Scientist Award (K02) seeks five years of salary support to provide release time to study the role of neuropeptides in mediating inflammatory and neuropathic pain. His integrative approach includes pharmacologic behavioral and molecular studies. The candidate obtained a Ph.D. at UCSD worked with Allan Basbaum at UCSF and is now an Associate Professor of Pharmacology at Tulane University. He has published 28 original articles (25 as first/last author) plus 7 invited reviews and received NRSA FIRST (R29) R21 and R01 grants to study pain and analgesia. His broad career goals include: 1. Extension of his current R01 into a well-conceived long-term research program that yields a new pharmacotherapy for chronic pain (e.g. an NPY receptor agonist); 2. Continued interactions with mentors that will foster his deeper understanding of the physiological cellular and biochemical mechanisms of chronic pain and its inhibition by neuropeptides; and 3. Continued collaborations and training in the utilization of molecular biological viral transfection and conditional transgenic mouse technologies so as to develop precise and targeted approaches to important questions in chronic pain research. Tulane remains rich in educational opportunities for intellectual growth and independence and provides outstanding resources to Dr. Taylor including laboratory space equipment behavioral suites in the vivarium and internal research funding. Tulane considers Dr. Taylor to be an integral part of its strong commitment to research and granted him early tenure in 2004. Contingent upon K02 funding the institution provides assurances that 85% of Dr.Taylor's time will be set aside for research and career development activities. The Research Plan focuses on the overall hypothesis that inflammatory or sensory nerve injury decreases presynaptic and postsynaptic elements of NPY signaling at the dorsal horn thereby facilitating pronociceptive neurotransmission and ultimately increasing allodynia and hyperalgesia. Aim #1 will determine the contribution of Y1 or Y2 receptors to the actions of NPY using new receptor subtype- selective antagonists and deletion mutant mice. Aim #2 will correlate injury-induced changes in behavior with NPY release and Y1 receptor expression. Aim #3 will use microdialysis and immunohistochemistry to determine whether NPY inhibits substance P release and dorsal horn nociresponsive neurons.

project_terms:
Absence of pain sensation;Acute;Address;Affect;Agonist;Amino Acids;Animal Model;Animals;Arthritis;Behavior;Behavioral;Biochemical;Biological;Cell membrane;Cerebrospinal Fluid;Collaborations;Confocal Microscopy;Coupled;Cytoplasm;Data;Doctor of Philosophy;Dose;Elements;Equipment;Fluorescence;Formalin;Fostering;Freund's Adjuvant;Funding;Gene Expression;Genes;Goals;Grant;Growth;Hyperalgesia;Hypersensitivity;Immunohistochemistry;Independent Scientist Award;Inflammation;Inflammatory;Injection of therapeutic agent;Injury;Institution;Intrathecal Space;Laboratories;Mechanics;Mediating;Mediator of activation protein;Mentors;Microdialysis;Modeling;Molecular;Morphology;Mutant Strains Mice;National Research Service Awards;Nerve;Neurons;Neuropathy;Neuropeptide Receptor;Neuropeptide Y Receptor;Neuropeptides;Neurotransmitters;Nociception;Pain;Pain Research;Peripheral;Peripheral nerve injury;Persistent pain;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Physiological;Posterior Horn Cells;Publishing;Radioimmunoassay;Receptor Activation;Research;Research Design;Research Project Grants;Resources;Role;Signal Transduction;Spinal;Stimulus;Substance P;Substance P Receptor;Sum;Technology;Testing;Time;Training;Transfection;Transgenic Mice;Universities;Viral;Wages;Work;afferent nerve;allodynia;career;career development;chronic pain;dorsal horn;gamma-Aminobutyric Acid;immunoreactivity;in vivo;inflammatory neuropathic pain;inhibitor/antagonist;nerve injury;neuropeptide Y;neuropeptide Y-Y1 receptor;neurotransmission;neurotransmitter release;nociceptive response;painful neuropathy;postsynaptic;presynaptic;professor;programs;receptor;receptor expression;receptor internalization;response;sensory stimulus;transmission process


application_id: 7885556
project_number: 5R01DA018822-05
project_title: Gated Carbon Nanotube Membrane Transdermal Drug Delivery
administering_ic: NIDA
award_notice_date: 2010-06-09
application_type: 5
activity_code: R01
ic: DA
serial_number: 018822
program_official: AIGNER, THOMAS G
project_start_date: 2006-09-30
project_end_date: 2015-01-31
study_section: Gene and Drug Delivery Systems Study Section[GDD]
contact_pi_person_id: 7929219
contact_pi: HINDS, BRUCE JACKSON
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
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
budget_start_date: 2010-07-01
project_terms:
Affinity;Alkanes;Alkanesulfonates;Binding (Molecular Function);Caliber;Carbon;Carbon Nanotubes;Cavia;Characteristics;Charge;Cigarette;Clonidine;Development;Devices;Dose;Drug Delivery Systems;Drug Kinetics;Electronics;Family suidae;Fentanyl;Film;Human;In Vitro;Incidence;Ionic Strengths;Iontophoresis;Ligands;Longitudinal Studies;Marketing;Membrane;Methods;Molecular;Nanotubes;Nicotine;Opiates;Patient-Controlled Analgesia;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Polymers;Polystyrenes;Production;Reaction Time;Regimen;Research Personnel;Role;Safety;Security;Skin;Smoker;Solutions;Solvents;System;Therapeutic;Transdermal substance administration;Withdrawal;aqueous;base;biomaterial compatibility;carboxylate;chronic pain;cost;craving;dosage;flexibility;improved;in vivo;irritation;programs;prototype;skin irritation;smoking cessation;success;voltage


application_id: 7885477
project_number: 5F30ES017730-02
project_title: Y-family DNA polymerases and cellular responses to benzo[a]pyrene
administering_ic: NIEHS
award_notice_date: 2010-06-18
opportunity_number: PA-05-151
application_type: 5
activity_code: F30
ic: ES
serial_number: 017730
program_official: HUMBLE, MICHAEL C
project_start_date: 2009-07-01
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZRG1-F10-S(21)L]
contact_pi_person_id: 9713011
contact_pi: KLARER, ALDEN C
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_terms:
Adenocarcinoma;Apoptosis;Base Pairing;Benzo(a)pyrene;Bypass;Cancer Etiology;Carcinogens;Cell Cycle Checkpoint;Cell physiology;Cells;Chemicals;Complex;DNA;DNA biosynthesis;DNA-Directed DNA Polymerase;Data;Development;Disease;Environmental Carcinogens;Enzymes;Eukaryotic Cell;Excision Repair;Face;Family;Fibroblasts;Frequencies (time pattern);Gene Expression;Generations;Genes;Goals;In Vitro;Incidence;Individual;Induced Mutation;Knowledge;Lesion;Lung Adenoma;Malignant Neoplasms;Malignant neoplasm of lung;Mammalian Cell;Molecular;Mouse Strains;Mus;Mutagenesis;Mutagens;Mutation;Mutation Spectra;Nucleotide Excision Repair;Pathway interactions;Polymerase;Proteins;Rad30 protein;Research;Role;Somatic Mutation;Tumor Suppressor Proteins;Ultraviolet Rays;Wild Type Mouse;Work;adduct;base;cancer chemoprevention;carcinogenesis;chemical carcinogen;chemical carcinogenesis;design;insight;mouse model;mutant;prevent;public health medicine (field);response


application_id: 7885411
project_number: 5R01HD053509-03
project_title: Transcriptional Coactivators and Pregnancy Outcomes
administering_ic: NICHD
award_notice_date: 2010-07-08
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 053509
program_official: HENKEN, DEBORAH B
project_start_date: 2008-07-01
project_end_date: 2013-06-30
study_section: Pregnancy and Neonatology Study Section[PN]
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
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): Two major medical health care issues are inexorably intertwined: a woman's health and prenatal development of her unborn child. Maternal folate status is one condition that has a profound influence on development of the central nervous system (CNS) and the incidence and recurrence of certain developmental disorders of the CNS (neural tube defects NTDs). While NTDs are amongst the most common human malformations the mechanisms by which folate exerts its ameliorative effect on these malformations or its role in normal morphogenesis of the CNS is not well understood. Extant data argue for interactions between folate status and developmental pathways controlled by specific transcriptional regulators. This proposal explores the nature of such interactions and consists of five hypothesis-driven specific aims linked together in order to present a cohesive picture of the molecular mechanisms by which specific translational coactivators mediate signal transduction in and contribute to development of the developing CNS. The overall hypothesis to be tested by the proposed specific aims is that normal CNS development in the mammalian embryo requires folate-mediated activation of a transcriptional complex functionally dependent on proper expression and integration of specific transcriptional coactivators. Specifically we propose that not only is proper expression of Folbp and transcriptional coactivators such as CBP p300 Cited2 Cart1 and AP-2 requisite for CNS formation but the integration of these molecules into a functional regulon is critical to normal CNS morphogenesis. Investments in research designed to reveal the causes of congenital anomalies such as NT defects provide excellent opportunities to meet Public Health Service requirements that biomedical science must pay social dividends. Experiments proposed in the current application seek to identify genes genetic variations and molecular pathways associated with susceptibility to NT defects and to understand signaling mechanisms associated with such disorders.NARRATIVE: In the United States every three minutes a baby is born with a birth defect! While neural tube defects (NTDs) are amongst the most common human malformations the mechanisms by which folic acid exerts its ameliorative effect on these malformations or its role in normal development of the neural tube is not well understood. Studies proposed in the current application should provide a better understanding of prenatal factors influencing the nutritional/health status of pregnant women and their impact on the health of the developing fetus particularly as it relates to NTDs.

project_terms:
Complex;Congenital Abnormality;Data;Defect;Development;E1A-associated p300 protein;EP300 gene;Embryo;Fetus;Folate;Folic Acid;Folic Acid Deficiency;Genes;Genetic Polymorphism;Genetic Transcription;Health;Health Status;Healthcare;Human;Incidence;Investments;Link;Mediating;Medical;Molecular;Morphogenesis;Nature;Neural Tube Defects;Neural Tube Development;Neural tube;Neuraxis;Nuclear;Nutritional;Pathway interactions;Pattern;Predisposition;Pregnancy Outcome;Pregnant Women;Proteins;Recurrence;Regulon;Research Design;Risk;Role;Science;Signal Transduction;TFAP2A gene;Testing;Transcription Coactivator;United States;United States Public Health Service;Variation (Genetics);Women's Health;developmental disease/disorder;genetic association;malformation;meetings;nervous system development;prenatal;research study;social;unborn child


application_id: 7884391
project_number: 5R01HL085777-03
project_title: Engineered Early Embryonic Cardiac Tissue
administering_ic: NHLBI
award_notice_date: 2010-05-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 085777
program_official: SCHRAMM, CHARLENE A
project_start_date: 2008-07-01
project_end_date: 2012-05-31
study_section: Cardiovascular Differentiation and Development Study Section[CDD]
contact_pi_person_id: 1902498
contact_pi: KELLER, BRADLEY BARTH
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We developed an Engineered Early Embryonic Cardiac Tissue termed EEECT using embryonic rat cardiac cells isolated during the period of cardiac morphogenesis in order to investigate the regulation of immature cardiomyocyte (CM) proliferation and differentiation and to generate implantable tissues with optimal properties for cardiac repair. Our EEECT construct preserves the unique proliferative and contractile properties of immature CM including a proliferative response to cyclic mechanical stretch. With prolonged culture EEECT acquires a post-natal phenotype (reduced proliferation and increased force production). Preliminary data show that EEECT implanted onto injured adult rat LV survive and improve LV diastolic and systolic function. In this revised R01-A2 proposal we identify molecular pathways that regulate EEECT CM proliferation and test our paradigm that EEECT is an optimal CM-rich tissue construct for cardiac repair. Specific Aim 1: Define molecular pathways that regulate EEECT CM proliferation during the transition from fetal to post-natal CM phenotype. We hypothesize that the regulation of CM proliferation and growth involves 2 concurrent processes: (1) CM proliferation to expand myocardial mass via p38 mitogen-activatedprotein kinase (p38MAPK) and Akt; and (2) CM sarcomere maturation and growth of non-proliferating CM via integrin-linked kinase (ILK) p38MAPK and Akt. We will use our in vitro EEECT model (generated from ED 14 embryonic rat cardiac cells) to define the impact of (1) cyclic mechanical loading; (2) stimulation or blockade of ILK p38MAPK and Akt; and (3) thyroid hormone treatment on CM proliferation and the phenotypic transition. Post-treatment characterization of EEECT will include: (1) histologic measures of CM proliferation differentiation and apoptosis; (2) biomechanical properties; (3) protein content and kinase activities; and (4) genome-wide changes in RNA transcript expression patterns. Specific Aim 2: Determine the fate of EEECT following implantation onto injured adult myocardium and the contribution of EEECT to recipient myocardial functional recovery and remodeling. We hypothesize implanted EEECT (1) display sustained CM proliferation and limited cell death; (2) positively contribute to the diastolic and systolic functional recovery of infarcted myocardium; and (3) become vascularized. We implant GFP+ transgenic rat EEECTs onto syngenic rat LV 2 weeks following myocardial infarction. Outcome assays at 3 days 2 weeks and 8 weeks include LV functional assay and histologic characterization of cell proliferation cell phenotype cell-cell coupling and vascularization. We further hypothesize that in vitro treatments that increase EEECT CM proliferation will increase in vivo EEECT CM survival and functional recovery. PUBLIC HEALTH RELEVANCE: Our proposed experiments first identify pathways that regulate cardiomyocyte proliferation and maturation within an Engineered Early Embryonic Cardiac Tissue (EEECT) generated using tissue culture and immature cardiac cells. We then evaluate the success of EEECT implantation onto the surface of the injured adult heart (myocardial infarction) as part of a cardiac repair and regeneration strategy.

project_terms:
Adrenergic Agents;Adult;Aftercare;Allogenic;Animals;Apoptosis;Autologous;Biological Assay;Biology;Biomechanics;Birth;Calcium;Cardiac;Cardiac Myocytes;Cardiomyoplasty;Cell Death;Cell Proliferation;Cell Proliferation Regulation;Cell Survival;Cell Therapy;Cell Transplants;Cells;Cicatrix;Clinical;Coupling;Data;Dimensions;Echocardiography;Embryo;Embryonic Development;Engineering;Environment;Extracellular Matrix;Failure (biologic function);Goals;Growth;Heart;Heart Transplantation;Histologic;Human;Hypertrophy;Hypoxia;Implant;In Vitro;Infarction;Injury;Left ventricular structure;MAPK14 gene;Measures;Mechanics;Mitogens;Molecular;Molecular Genetics;Morphogenesis;Myocardial;Myocardial Infarction;Myocardium;Natural regeneration;Outcome;Pathway interactions;Pattern;Phenotype;Phosphotransferases;Population;Process;Production;Proliferating;Property;Proteins;Published Comment;RNA;Rattus;Recovery;Recovery of Function;Regulation;Sarcomeres;Signal Pathway;Stimulus;Stretching;Surface;Testing;Thyroid Hormones;Tissue Engineering;Tissue Model;Tissues;Transcript;Transgenic Organisms;Translating;Transplantation;Treatment Protocols;Vascularization;adrenergic;extracellular;fetal;genome-wide;human MAPK14 protein;implantation;improved;in vivo;injured;insight;integrin-linked kinase;mitogen-activated protein kinase p38;neovascularization;pressure;public health relevance;repaired;research study;response;response to injury;success;tissue culture

public_health_relevance:
Our proposed experiments first identify pathways that regulate cardiomyocyte proliferation and maturationwithin an Engineered Early Embryonic Cardiac Tissue (EEECT) generated using tissue culture and immaturecardiac cells. We then evaluate the success of EEECT implantation onto the surface of the injured adult heart(myocardial infarction) as part of a cardiac repair and regeneration strategy.


application_id: 7884381
project_number: 5R01DK081555-02
project_title: Upstream Stimulatory Factor 2 regulation of renin in diabetic nephropathy
administering_ic: NIDDK
award_notice_date: 2010-09-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 081555
program_official: NIHALANI, DEEPAK
project_start_date: 2009-09-01
project_end_date: 2014-08-31
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
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): Diabetic nephropathy is the most common cause of end-stage renal failure and is highly prevalent in both type 1 and type 2 diabetics. Hyperglycemia and the activation of the intrarenal renin-angiotensin system (RAS) in diabetes have been suggested to play a critical role in the pathogenesis of diabetic nephropathy. However the mechanisms for the effectiveness of inhibitors of the RAS or for angiotensin II as a mediator of diabetic nephropathy are not well defined. Transforming growth factor- (TGF-) is a major effector leading to renal fibrosis in response to hyperglycemia. Preliminary data demonstrate that Upstream Stimulatory Factor (USF2) is an important transcription factor in high glucose-induced TGF- production in mesangial cells. Importantly USF2 expression is increased in the kidneys of diabetic mice and correlates with the glomerular mesangial matrix expansion. Furthermore over-expression of USF2 accelerates the development of diabetic nephropathy in a type 1 diabetic mouse model supporting the role of this transcription factor in the development of diabetic nephropathy. Our preliminary studies describe a novel effect of USF2 to promote renin gene expression and angiotensin II formation in mesangial cells. This effect of USF2 was linked to glucose-induced regulation of TGF- production suggesting that this pathway may contribute to the development of diabetic nephropathy. The working hypothesis of this proposal is that USF2 stimulates the renal RAS to promote production of TGF- and the development of diabetic nephropathy. The proposed studies will define the role of USF2 in the development of diabetic nephropathy focusing on regulation of mesangial cell renin as the mechanistic target. In aim 1 the mechanisms by which USF2 regulates renin gene expression and angiotensin II production in mesangial cells under normal or high glucose conditions will be determined. In aim 2 the role of USF2-mediated renin expression and angiotensin II production in high glucose induced TGF- levels and extracellular matrix protein (ECM) expression in mesangial cells will be defined. In aim 3 the role of USF2-mediated up-regulation of the renal RAS in the development of diabetic nephropathy in vivo will be determined. Our approach utilizes both in vitro and in vivo studies to provide new information on the mechanisms of activation of the intrarenal RAS system in diabetes and will lead to the development of novel therapies to ameliorate this major complication of diabetes. Public health relevance: Diabetic nephropathy is the most common cause of end-stage renal failure and is highly prevalent in both type 1 and type 2 diabetics. The proposed studies will provide new information on the mechanisms of activation of the intrarenal renin-angiotensin system in diabetes and will lead to the development of novel therapies to ameliorate this major complication of diabetes.

project_terms:
Albumins;Angiotensin II;Complications of Diabetes Mellitus;Data;Deposition;Development;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Effectiveness;End stage renal failure;Excretory function;Exhibits;Extracellular Matrix;Extracellular Matrix Proteins;Fibrosis;Gene Expression;Gene Proteins;Genes;Glomerular Mesangial Cell;Glucose;Hyperglycemia;Hypertrophy;In Vitro;Injection of therapeutic agent;Insulin-Dependent Diabetes Mellitus;Kidney;Kidney Diseases;Lead;Link;Losartan;Mediating;Mediator of activation protein;Mus;Pathogenesis;Pathway interactions;Physiological;Plasma;Play;Production;Proteins;Regulation;Relative (related person);Renal function;Renin;Renin-Angiotensin System;Role;Small Interfering RNA;Streptozocin;Structure;System;Testing;Transforming Growth Factors;Transgenic Organisms;Up-Regulation (Physiology);Wild Type Mouse;Work;aliskiren;diabetic;glomerular basement membrane;glomerular function;glomerulosclerosis;human USF2 protein;in vivo;inhibitor/antagonist;mesangial cell;mouse model;novel;protein expression;public health relevance;receptor;response;transcription factor;transcription factor USF;type I and type II diabetes;type I diabetic;urinary


application_id: 7884297
project_number: 5R01NS053470-04
project_title: Designer Proteoglycans for Central Nervous System Injury
administering_ic: NINDS
award_notice_date: 2010-07-09
application_type: 5
activity_code: R01
ic: NS
serial_number: 053470
program_official: KLEITMAN, NAOMI
project_start_date: 2007-08-01
project_end_date: 2012-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7875161
contact_pi: SNOW, DIANE M
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-08-01
project_abstract:
DESCRIPTION (provided by applicant): In the adult mammalian brain and spinal cord neuronal injury results in failed regeneration in part due to the upregulation of chondroitin sulfate proteoglycans (CSPGs). The majority of CSPGs originate from reactive astrocytes of the glial scar surrounding the lesion. The glial scar is beneficial for the recovering nervous system and should not be "excised" but axonal growth could be promoted if the expression of specific inhibitory portions of CSPGs could be targeted selectively. Our previous data indicate that neuronal inhibition is due to specific CSPG microheterogeneities and to the specific configurations of CSPGs predicted by their structure and by the molecules to which they bind. Our goal is to identify the most significant of the CSPG motifs with respect to neurite inhibition and regeneration and specifically to manipulate these moieties to promote regeneration. To this end we and our collaborators have engineered 1) an array of CSPG isoforms and mutants we call "Designer PCs" 2) a variety of unique bioassays to express CSPGs including a novel model of the glial scar in vitro and 3) imaging methods to measure subtle features of nerve responses to CSPGs. The hypothesis of this proposal is: Identification and manipulation of specific inhibitory CSPG motifs using designer PGs and novel models of the glial scar will promote plasticity and regeneration in vitro and in vivo. We propose three Specific Aims that represent independent but interrelated studies to test this hypothesis. One we will determine the expression and relative abundance of specific inhibitory CSPG types and posttranslational modifications or core protein domains by reactive astrocytes in vitro. Two we will determine the inhibitory potential for specific CSPG posttranslational modifications or core protein domains by establishing an inhibitory quotient to evaluate the responses of adult neurons in vitro. Three we will manipulate specific inhibitory moieties of CSPGs to promote neuronal regeneration of adult neurons in vivo. The long term goal of this study is to identify the mechanism(s) of CSPG-induced inhibition following brain and spinal cord injury. The significance of the studies lies in the tremendous potential for translational application through the manipulation of specific CSPG motifs in injured patients providing a therapeutic avenue to stimulate neuronal plasticity facilitate reconnectivity of injured neurons and accomplish restoration of function.

project_terms:
Adult;Astrocytes;Behavior;Binding (Molecular Function);Biological Assay;Brain;Chondroitin Sulfate Proteoglycan;Cicatrix;Core Protein;Cues;Data;Engineering;Family member;Goals;Growth;In Vitro;Injury;Knowledge;Lesion;Link;Measures;Modeling;Modification;Natural regeneration;Nerve;Nervous System Trauma;Nervous system structure;Neurites;Neuronal Injury;Neuronal Plasticity;Neurons;Patients;Pattern;Post-Translational Protein Processing;Protein Family;Protein Isoforms;Proteoglycan;Regulation;Relative (related person);Reporting;Site;Spinal Cord;Structure;Tertiary Protein Structure;Testing;Therapeutic;Up-Regulation (Physiology);axon growth;central nervous system injury;clinical application;glycosylation;imaging modality;in vivo;injured;innovation;mutant;novel;progesterone 11-hemisuccinate-(2-iodohistamine);proteoglycan core protein;response;restoration;spinal cord and brain injury;sulfation


application_id: 7883842
project_number: 1R01MH082762-01A2
project_title: 2/2-Computer-Assisted Cognitive-Behavior Therapy for Depression
administering_ic: NIMH
award_notice_date: 2010-06-16
opportunity_number: PAR-09-153
application_type: 1
activity_code: R01
ic: MH
serial_number: 082762
suffix: A2
program_official: PEARSON, JANE L
project_start_date: 2010-06-16
project_end_date: 2014-03-31
study_section: Interventions Committee for Adult Disorders[ITVA]
contact_pi_person_id: 9075017
contact_pi: WRIGHT, JESSE H.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
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): We propose a two center randomized controlled trial evaluating the efficacy and cost-effectiveness of computer-assisted cognitive-behavior therapy (CCBT) for outpatients with major depressive disorder (MDD). Results of a preliminary study indicated that despite reducing the amount of therapist contact by about 50% CCBT was at least as effective as an 8 week course of conventional individual CBT on depression outcomes with greater effects on dysfunctional attitudes and knowledge about CBT. We now propose to conduct a more rigorous test of the therapeutic equivalence and cost-effectiveness of CCBT versus a full 16 week 20 session course of individual CBT which provides three times the amount of therapeutic contact. A total of 172 male and female outpatients (86 per site) meeting SCID/DSM-IV criteria for MDD will be randomized across five years. Outcomes will be assessed by independent evaluators without knowledge of the treatment received. The study is designed to have the statistical power to test the equivalence of CCBT and the full course of CBT at both the end of acute phase therapy and across 6 months of follow-up. In addition to effects on depressive symptoms and categorical outcomes (i.e. response and remission rates) dependent variables will include measures of dysfunctional attitudes social functioning quality of life and health care costs and utilization. It is predicted that: 1) CCBT will be equivalent to CBT at week 16 and across the 6 month follow-up; and 2) CCBT will be significantly more cost-effective than CBT. Secondary aims include testing potential moderators of treatment outcome and the predicted absence of site differences (as an indicator of disseminability). This trial has significant implications for the public health because it will provide a rigorous test the clinical utility of CCBT against a model of conventional individual therapy that offers three times as much clinical contact. If equivalence and cost- effectiveness are demonstrated the proposed research will set the stage for larger scale studies evaluating broader dissemination of CCBT.  
  
PUBLIC HEALTH RELEVANCE: Although Cognitive Behavior Therapy (CBT) is an effective treatment for major depressive disorder its utility is limited by cost and availability of trained therapists. Computer-assisted delivery of this therapy (CCBT) has shown promise and may offer similar benefits as CBT with as little as one third the amount of therapist time. The proposed study will test the therapeutic equivalence and cost-effectiveness of CCBT versus CBT across a 16 week acute phase and a 6 month follow-up.

project_terms:
Acute;Attitude;Characteristics;Clinical;Cognitive;Cognitive Therapy;Computer Assisted;Computer-Assisted Therapy;Control Groups;Data;Data Analyses;Development;Disease remission;Elements;Female;Grant;Health Care Costs;Hour;Individual;Intervention;Investigation;Knowledge;Major Depressive Disorder;Measures;Mental Depression;Methods;Modeling;Multimedia;Outcome;Outpatients;Patient Preferences;Patients;Pennsylvania;Phase;Protocols documentation;Psychotherapy;Quality of life;Randomized;Randomized Controlled Trials;Recruitment Activity;Relapse;Research;Research Design;Sampling;Services;Site;Social Functioning;Staging;Testing;Therapeutic;Thinking function;Time;Training;Treatment outcome;Universities;Waiting Lists;base;behavior change;clinically significant;comparative efficacy;conventional therapy;cost;cost effectiveness;depressive symptoms;design;effective therapy;efficacy testing;experience;follow-up;health care service utilization;improved;male;meetings;programs;public health medicine (field);public health relevance;response


application_id: 7883683
project_number: 5R01DA025100-03
project_title: High-activity mutants of cocaine esterase for treatment of drug addiction
administering_ic: NIDA
award_notice_date: 2010-06-04
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 025100
program_official: SHIH, MING L
project_start_date: 2008-08-15
project_end_date: 2013-06-30
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: LANDRY, DONALD W;WOODS, JAMES 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 PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Enhancing cocaine metabolism by administration of cocaine esterases has been recognized as a promising treatment strategy for cocaine overdose and addiction. The esterase CocE is the most efficient native enzyme for metabolizing naturally occurring (-)-cocaine yet identified. Through catalysis of (-)-cocaine hydrolysis CocE can both prevent and reverse extreme (-)- cocaine toxicity in rodent models and it has the potential to be developed into a chemically useful antagonist of the toxic and behavioral effects of (-)-cocaine. In order to optimize the efficacy of this potential anti-cocaine medication and minimize its possible side effects (particularly immunogenicity) we propose to improve the catalytic efficiency of CocE against (-)- cocaine. The higher the catalytic efficiency of the enzyme against (-)-cocaine the lower the dose required to achieve therapeutic effectiveness and the decrease in dose can reduce the overall immunological response. Hence we will focus on the rational design discovery and preclinical testing of CocE mutants with an improved catalytic efficiency against (-)-cocaine. The rational design of high-activity mutants of CocE against (-)-cocaine requires a detailed understanding of the mechanism for CocE-catalyzed hydrolysis of cocaine. This mechanism can be understood by performing computational studies using the state-of-the-art computational techniques of molecular modeling simulation and calculation. The specific aims include: (1) Elucidation of the detailed mechanism and reaction coordinate and the corresponding free energy profiles for CocE-catalyzed hydrolysis of cocaine by performing quantum mechanical (QM) calculations hybrid quantum mechanical/molecular mechanical (QM/MM) calculations and molecular dynamics (MD) simulations etc. (2) Design discovery and testing of CocE mutants with an improved catalytic efficiency against (-)-cocaine by using a recently developed novel computational design approach based on the transition state modeling and simulation to computationally evaluate a large number of hypothetical CocE mutants followed by wet experimental tests including site-directed mutagenesis protein expression and purification and in vitro and in vivo activity tests. The long-term objective of this investigation will be to eventually develop an efficient anti-cocaine medication using a high-activity mutant of CocE. PUBLIC HEALTH RELEVANCE: Enhancing cocaine metabolism by administration of cocaine esterase (CocE) has been recognized as a promising treatment strategy for cocaine overdose and addiction. The high-activity mutants of CocE to be designed and discovered in this project will eventually lead to an efficient anti-cocaine medication.

project_terms:
Adverse effects;Arts;Behavioral;Catalysis;Cocaine;Cocaine Dependences;Computational Technique;Coupled;Dose;Drug Addiction;Enzymes;Evaluation;Free Energy;Hybrids;Hydrolysis;In Vitro;Investigation;Lead;Mechanics;Metabolism;Modeling;Molecular;Molecular Models;Overdose;Performance;Pharmaceutical Preparations;Preclinical Testing;Process;Protocols documentation;Reaction;Rodent Model;Roentgen Rays;Site-Directed Mutagenesis;Structure;Testing;Toxic effect;addiction;base;cocaine esterase;cocaine overdose;cocaine use;computer studies;design;esterase;immunogenicity;improved;in vivo;models and simulation;molecular dynamics;molecular modeling;mutant;novel;preclinical study;prevent;protein expression;public health relevance;quantum;response;therapeutic effectiveness;three dimensional structure;treatment strategy


application_id: 7883660
project_number: 5R21AT005235-02
project_title: Inhibition of Cholesterol Synthesis by Green and Black Tea
administering_ic: NCCIH
award_notice_date: 2010-06-10
opportunity_number: PA-08-185
application_type: 5
activity_code: R21
ic: AT
serial_number: 005235
program_official: WEBER, WENDY J
project_start_date: 2009-07-01
project_end_date: 2013-06-30
study_section: ZAT1-PK(03)
contact_pi_person_id: 1859126
contact_pi: PORTER, TODD D
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): "Functional foods" herbal and other botanical products and nutritional supplements have gained great popularity among the public as safe and effective means to treat chronic and acute diseases. As hypercholesterolemia is a widespread problem for which there is great interest in alternative medicines the demonstrated ability of black tea to decrease serum cholesterol levels is of particular interest. Similarly green tea has been shown to be hypocholesterolemic in animal studies. The mechanism by which these safe and widely consumed beverages act to lower cholesterol has not yet been elucidated. Although most current evidence indicates that tea polyphenols reduce the absorption of dietary and biliary cholesterol our recent studies with hepatoma cells indicate that green and black tea extracts also decrease cholesterol synthesis via both direct enzyme inhibition and by suppression of HMG-CoA reductase activity. Knowledge of how tea consumption lowers cholesterol levels is essential to understanding the benefits and potential adverse effects of its intake particularly in combination with prescription pharmaceuticals including the statin drugs which similarly inhibit cholesterol synthesis at HMG-CoA reductase. As our current studies indicate that tea extracts cause the activation of AMP-kinase to suppress HMG-CoA reductase activity the objectives of this application are to determine if tea extracts directly activate AMP-kinase or if upstream signaling pathways are involved; and to determine if tea suppresses cholesterol synthesis in vivo. These studies should delineate the intracellular mechanism by which tea compounds suppress cholesterol synthesis and elucidate the extent to which suppression of cholesterol synthesis contributes to the hypocholesterolemic effect of green and black tea. These studies should establish a solid mechanistic understanding of how tea decreases cholesterol synthesis and lowers blood cholesterol levels and given the developing recognition of the role of AMP-kinase in diabetes may also open new pathways to the management of diabetes and "metabolic syndrome".

project_terms:
5'-AMP-activated protein kinase;Acute Disease;Adverse effects;Alternative Medicine;Animals;Antibodies;Beverages;Biliary;Biological Assay;Black Tea;Blood;Botanicals;Cells;Cholesterol;Cholesterol Synthesis Inhibition;Chronic;Consumption;Cyclic AMP-Dependent Protein Kinases;Deacetylase;Diabetes Mellitus;Dietary Supplements;Dose;Enzyme Activation;Enzyme Inhibition;Enzymes;Green tea (dietary);Hepatic;Hydroxymethylglutaryl-CoA reductase;Immunoblotting;Intake;Knowledge;LDL Cholesterol Lipoproteins;Lead;Liver;Measures;Mediating;Metabolic syndrome;Monitor;Mus;Oral;Pathway interactions;Pharmaceutical Preparations;Pharmacologic Substance;Phosphorylation;Phosphotransferases;Preparation;Protein Kinase;Research;Resveratrol;Role;STK11 gene;Serum;Signal Pathway;Small Interfering RNA;Solid;Sterols;Tea;Water;absorption;adenylate kinase;diabetes management;functional food;hepatoma cell;hypercholesterolemia;in vivo;interest;knock-down;man;polyphenol;upstream kinase

public_health_relevance:
PROJECT NARRATIVEInhibition of Cholesterol Synthesis by Green and Black Tea"Functional foods" herbal and other botanical products and nutritional supplements have gained greatpopularity among the public as safe and effective means to treat chronic and acute diseases. Ashypercholesterolemia is a widespread problem for which there is great interest in alternative medicines thedemonstrated ability of tea to decrease serum cholesterol levels is of particular interest. Preliminary studiesdemonstrate that tea decreases cholesterol synthesis by suppressing the activity of a key enzyme in thebiosynthetic pathway; the proposed studies will elucidate the mechanism by which tea effects this suppressionand will determine the extent to which tea suppresses cholesterol synthesis in whole animals after oralconsumption.


application_id: 7883398
project_number: 5R01EY012998-10
project_title: Determinants of extraocular muscle function
administering_ic: NEI
award_notice_date: 2010-07-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 012998
program_official: ARAJ, HOUMAM H
project_start_date: 2001-03-01
project_end_date: 2012-07-31
study_section: Special Emphasis Panel[ZRG1-MOSS-L(07)M]
contact_pi_person_id: 6197585
contact_pi: ANDRADE, FRANCISCO H
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The ocular motor system is arguably the best understood mammalian motor system. However the extraocular muscles its effector arms remain somewhat of a black box. From a peculiar phenotype and extreme functional profile to a disparate response to some neuromuscular disorders these small muscles deviate from the skeletal muscle stereotype. Our results have demonstrated that the extraocular muscles have alternative arrangements for metabolic pathways considered vital for other skeletal muscles. Moreover our pilot studies suggest that their mitochondria have unique properties as well a fact that may explain their susceptibility to some mitochondrial myopathies. In this project we will test the hypothesis that mitochondria are functionally different in the extraocular muscles and their content and properties are determined by visual experience and altered by aging. We will combine well-established functional and biochemical assays with models of visual deprivation and aging to achieve the following aims: (1) determine the factors that limit mitochondrial function in the extraocular muscles; (2) test whether extraocular muscle mitochondrial content and function are influenced by postnatal visual experience; and (3) determine how aging alters mitochondrial content and function in the extraocular muscles. The results will address three important gaps in our understanding of the basic biology of the extraocular muscles: the functional properties of their mitochondria the development of their metabolic properties in the postnatal period and aging. Therefore we expect that the new knowledge will be applicable to disorders of ocular motility in the young (strabismus) and the aged (mitochondrial myopathies).  PUBLIC HEALTH RELEVANCE: This project will study how the mitochondria the cellular energy factories of the cells are different in the small muscles that move the eyes. It will also demonstrate how normal vision early in life is very important to allow the eye muscles to achieve their capacity to generate energy and sustain high activity levels. Finally these studies will explore the deleterious consequences of aging on eye muscle function.

project_terms:
Academy;Address;Adult;Aerobic;Affect;Age;Aging;American;Biochemical;Biogenesis;Biological Assay;Biology;Boxing;Buffers;Calcium;Cell Respiration;Cells;Characteristics;Child;Chronic progressive external ophthalmoplegia;Clinical;Complex;Creatine Kinase;Data;Dependence;Development;Electron Transport;Eye;Eye Movements;Fatigue;Incidence;Knowledge;Life;Limb structure;Metabolic;Metabolic Pathway;Mitochondria;Mitochondrial Myopathies;Modeling;Motor;Muscle;Muscle Mitochondria;Muscle Proteins;Muscle function;Myosin ATPase;Neuromuscular Diseases;Ocular Motility Disorders;Pediatrics;Phenotype;Pilot Projects;Predisposition;Property;Protein Isoforms;Research Personnel;Resistance;Resolution;Sensory;Skeletal muscle structure;Stereotyping;Strabismus;System;Testing;Time;Training;Vision;Visual;age related;aged;arm;cell motility;critical period;dark rearing;early experience;end of life;experience;oculomotor;orbit muscle;postnatal;programs;protein complex;public health relevance;research study;respiratory;response;visual deprivation


application_id: 7883397
project_number: 5R01EY017594-03
project_title: The Role of CaMKII in Cell Death and Survival Responses of Retinal Ganglion Cells
administering_ic: NEI
award_notice_date: 2010-05-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 017594
program_official: GREENWELL, THOMAS
project_start_date: 2008-06-01
project_end_date: 2012-05-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
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 signal transduction and gene regulatory events which occur downstream of the precipitating causes of retinal diseases is largely unknown. Yet these downstream sites would be excellent targets for interventional therapies. The long term goal of the proposed research is to define the role of calmodulin dependent protein kinase II (CaMKII) which is likely downstream of the initiating events in eye diseases like retinal ischemia. CaMKII is upstream of the cell death and survival pathways in retinal ganglion cells (RGCs). We know that when challenged with glutamate receptor agonists: 1) retinal cytoplasmic CaMKII1 becomes autophosphorylated; 2) there is an increase in the alternatively spliced nuclear transcript CaMKII1B; 3) caspase-3 becomes activated and 4) cells in the inner nuclear and ganglion cell layers die. We have demonstrated that the specific inhibitor of CaMKII autocamtide inhibitory peptide (AIP) blocks these changes (1 3 and 4) and protects all cells from cell death. Pilot data with the aid of a cell line indicates that the AIP promotes the secretion of brain derived neurotrophic factor (BDNF) which may aid the survival of challenged cells. We also know that an elevated level of CaMKII1B (2) is associated with enhanced transcription of BDNF. Since glutamate is implicated in retinal ischemia and CaMKII1 is also activated in this condition we hypothesize that CaMKII1 plays an important role in pathways involved in the death and survival responses of RGCs during retinal ischemia. This will be tested with methods which include RNA- interference for the CaMKII1B transcript. We will use a rat retinal ischemia-reperfusion model as well as primary cultured rat RGCs and ex vivo retinal explants. Aim 1 will determine the time frame in which AIP protects RGCs during/after ischemia. Aim 2 will explore the role of cytoplasmic CaMKII in regulating caspase-3 activation NF:B translocation and BDNF release in RGC/retinas. Aim 3 will explore the role of nuclear CaMKII1 in cell death/survival and the underlying mechanisms. The results of these studies will provide important insights into the signal transduction pathways and gene regulatory networks that control death and survival responses of RGCs which will be of relevance to retinal ischemia. PUBLIC HEALTH RELEVANCE: Retinal ischemia a common clinical entity that has been widely studied because of its proposed role in for example retinal and choroidal vessel occlusion anterior ischemic optic neuropathy glaucoma and diabetic retinopathy etc remains a common cause of blindness in the developed world due to relatively ineffective treatment. We propose to explore the signal transduction pathways linked to gene regulatory networks which control cell death and survival processes in rat retinal ganglion cells whose death is a major contributing factor for visual impairment in these diseases. Knowledge of such pathways and networks is important for the development of practical therapeutic interventions.

project_terms:
Acute;Affect;Agonist;Animal Model;Anterior Ischemic Optic Neuropathy;Blindness;Brain-Derived Neurotrophic Factor;Calcium/calmodulin-dependent protein kinase;Cell Death;Cell Line;Cell Survival;Cells;Cessation of life;Clinical;Data;Development;Diabetic Retinopathy;Disease;Equilibrium;Event;Eye diseases;Ganglion Cell Layer;Gene Targeting;Genes;Genetic Transcription;Glaucoma;Glutamate Receptor;Glutamates;Goals;In Vitro;Injection of therapeutic agent;Intraperitoneal Injections;Ischemia;Knowledge;Laboratories;Link;Mediating;Methods;Modeling;Nuclear;Pathway interactions;Patients;Peptides;Phosphotransferases;Play;Process;Protein Isoforms;RNA Interference;RNA Splicing;Rattus;Regulator Genes;Reperfusion Therapy;Research;Retina;Retinal;Retinal Diseases;Retinal Ganglion Cells;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Site;Testing;Therapeutic Intervention;Time;Transcript;Transduction Gene;Visual impairment;autocrine;calmodulin-dependent protein kinase II;caspase;caspase-3;inhibitor/antagonist;insight;neuroprotection;paracrine;prospective;public health relevance;response;retinal ischemia;retinal neuron;transcription factor


application_id: 7882728
project_number: 3U01ES015673-05S1
project_title: Novel Therapies for Chlorine-Induced Lung Injury
administering_ic: NIEHS
award_notice_date: 2009-06-29
opportunity_number: RFA-NS-06-004
application_type: 3
activity_code: U01
ic: ES
serial_number: 015673
suffix: S1
program_official: HEACOCK, MICHELLE
project_start_date: 2006-09-29
project_end_date: 2010-05-31
study_section: ZNS1-SRB-R(22)
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY 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
project_abstract:
DESCRIPTION (provided by applicant): Acute high-level exposures to chemicals that damage the respiratory tract can cause life-threatening lung injury. Chlorine gas is a highly toxic respiratory irritant that when inhaled causes cellular injury alveolar- capillary barrier disruption inflammation and pulmonary edema. We are investigating mechanisms by which G proteins which are ubiquitous intracellular signaling molecules regulate lung injury inflammation and repair. During the course of the proposed research we will investigate how G protein-mediated signaling pathways regulate injury and inflammation that are induced when lungs or lung cells are exposed to chlorine gas. We will then apply the information gained from these studies to develop novel treatment strategies based on modulation of G protein function to ameliorate acute lung injury. G protein coupled receptors (GPCRs) which control cellular homeostasis and responses to environmental stimuli are activated by a variety of neuropeptides inflammatory mediators and hormones that are released following tissue injury. GPCRs activate intracellular signaling pathways by stimulating G proteins that have been classified into four families: Gq Gs Gj and Gi2. We have observed that activation of Gq in lung epithelial cells stimulates proinflammatory gene expression whereas activation of Gs promotes increased survival following injury. In the proposed experiments we will use manipulation of Gq and Gs signaling pathways as potential therapeutic measures to treat acute lung injury induced by inhalation of chlorine gas. In Specific Aim 1 we will examine mechanisms by which Gq signaling promotes activation of the proinflammatory transcription factor NF-KB and Gs inhibits chlorine toxicity in cultured epithelial and endothelial cells. In Specific Aim 2 we will determine using an inducible cell-specific knockout mouse model whether Gq signaling in lung epithelial cells is a therapeutic target for ameliorating acute lung injury. In Specific Aim 3 we will develop treatment strategies including cell-soluble Gq inhibitory peptides and Gq siRNA for chlorine-induced lung injury based on inhibition of Gq function. In Specific Aim 4 we will optimize the in vivo delivery of therapeutic agents for chlorine-induced lung injury based on inhibition of Gq function and stimulation signaling pathways downstream of Gs. This application is submitted in response to RFA-NS-06-004 "Countermeasures Against Chemical Threats." The proposed experiments are designed to understand how inhalation of a toxic chemical injures the lung and based on this information to develop novel ways to treat or prevent acute lung injury. This type of research is sought through the RFA because of concerns that U. S. civilians could be adversely affected by highly toxic chemicals released intentionally in terrorist attacks or unintentionally in industrial accidents or natural disasters.

project_terms:
Acute;Adenylate Cyclase;Aerosols;Affect;Agreement;Alveolar;Animal Model;Antioxidants;Area;Arts;Blood capillaries;Bradykinin Receptor;Breathing;Buffers;Calcium;Cell Culture Techniques;Cell Survival;Cells;Chemical Injury;Chemicals;Chlorine;Cyclic AMP;Distal;Dose;Endothelial Cells;Epithelial;Epithelial Cells;Exposure to;Family;G alpha q Protein;G-Protein-Coupled Receptors;GTP-Binding Proteins;Gases;Gene Expression;Glutathione;Goals;Health Hazards;Heterotrimeric GTP-Binding Proteins;Homeostasis;Hormones;Human;Industrial Accidents;Infection;Inflammation;Inflammation Mediators;Inflammatory;Injury;Inositol;Irritants;Knockout Mice;Lead;Life;Ligand Binding;Lung;Lung Inflammation;Lung Injury Acute;Measures;Mediating;Mediator of activation protein;Modeling;Morbidity - disease rate;Natural Disasters;Neuropeptide Receptor;Neuropeptides;Nose;Outcome;Paper;Pathway interactions;Peptides;Phosphodiesterase Inhibitors;Phospholipase;Phospholipase C;Plastics;Platelet Activating Factor;Poisons;Population;Process;Production;Property;Prostaglandins;Proteins;Pulmonary Edema;Ras/Raf;Research;Research Personnel;Respiratory System;Respiratory tract structure;Role;Route;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;Small Interfering RNA;Solvents;Stimulus;Substance P;Substance P Receptor;Testing;Text;Therapeutic;Therapeutic Agents;Tissues;Toxic effect;United States;Up-Regulation (Physiology);base;capillary;cell injury;chemical release;chlorine gas;design;drinking water;established cell line;improved;in vivo;injured;lung basal segment;lung injury;mouse model;novel;peptide G;prevent;programs;protective effect;protein function;receptor;receptor coupling;repaired;research study;respiratory;response;surfactant;therapeutic target;toxicant;transcription factor;treatment strategy;tripolyphosphate


application_id: 7882473
project_number: 5R01HD056002-03
project_title: Sensory-driven motor recovery in poorly recovered subacute stroke patients
administering_ic: NICHD
award_notice_date: 2010-07-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 056002
program_official: ANSEL, BETH
project_start_date: 2008-09-01
project_end_date: 2013-06-30
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 7375465
contact_pi: SAWAKI-ADAMS, LUMY
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
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:
Activities of Daily Living;Acute;Address;Adult;Affect;Animals;Area;Behavioral;Brain;Brain Injuries;Chronic;Complex;Control Groups;Coupled;Data;Disease;Effectiveness;Future;Goals;Hand;Human;Intervention;Lead;Learning;Maps;Measures;Metacarpophalangeal joint structure;Modeling;Motor;Motor Cortex;Motor Skills;Motor output;Muscle;Nerve;Neurologic;Neurorehabilitation;Patients;Peripheral Nerve Stimulation;Persons;Phase;Plastics;Play;Quality of life;Recovery;Recovery of Function;Rehabilitation therapy;Research;Research Project Grants;Risk;Role;Sensory;Solid;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Training;Transcranial magnetic stimulation;United States;Upper Extremity;Wolves;Work;Wrist;acute stroke;animal data;chronic stroke;constraint induced therapy;disability;experience;extensor digitorum;improved;memory process;motor deficit;motor impairment;neurophysiology;post stroke;public health relevance;randomized trial;restoration;sensory cortex;skill acquisition;stroke;stroke rehabilitation


application_id: 7882331
project_number: 5T32DA022738-05
project_title: Therapeutic Strategies for Neurodegeneration Training Grant
project_terms: Grant;Nerve Degeneration;Therapeutic;Training
administering_ic: NIDA
award_notice_date: 2010-07-14
opportunity_number: RFA-DA-06-008
application_type: 5
activity_code: T32
ic: DA
serial_number: 022738
program_official: BABECKI, BETH
project_start_date: 2006-09-26
project_end_date: 2012-06-30
study_section: ZDA1-KXN-G(08)
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
project_abstract:
DESCRIPTION (provided by applicant):   
  
This application is in response to RFA-DA-06-008 entitled Training in Translational Research in Neurobiology of Disease (T32). The overall goal of the proposed Therapeutic Strategies for Neurodegeneration Training Program is to prepare promising predoctoral scholars (graduate students) postdoctoral scholars and clinical scholars for successful careers in translational neuroscience aimed at the discovery and development of disease-modifying pharmacological and genetic therapies for devastating neurodegenerative disorders or diseases such as spinal cord injury (SCI) traumatic brain injury (TBI) stroke and Parkinson's Disease (PD). We will provide broad-based training in modern research concepts regarding the pathophysiology of these and other neurodegenerative disorders and potential disease modifying molecular targets that can drive the discovery of pharmacological and gene therapeutic strategies by which the devastating effects of these disorders can be ameliorated. These strategies will include both "neuroprotective" and "neurorestorative" approaches. Funding is requested for 5 Predoctoral Scholars each year for 5 years. Beginning in year 2 funds are requested for 1 Postdoctoral Scholar and 1 Clinical Trainee. In the case of the latter the purpose is to provide a 1 year fellowship for a late stage neurology or neurosurgery resident a clinical fellow or a young Assistant Professor to spend a year cross-training in a basic research laboratory. Fourteen basic science and 5 clinical faculty from two basic science departments (Anatomy and Neurobiology and Physiology) two clinical departments (Neurology and Neurosurgery) and three centers (Spinal Cord & Brain Injury Research Center Morris K. Udall Parkinson's Disease Research Center and the Sanders-Brown Center on Aging) will participate in this Training Program. The training program for all of the trainees involves a strong emphasis on translationally-focused therapeutic discovery basic research. For the Predoctoral and Postdoctoral Scholars each will be expected to complete a multi faceted Clinical Tutorial specifically designed to be relevant to the disease focus of their research. All of the trainees will have the opportunity to participate in a rich offering of didactic course work seminars annual translationally-oriented research symposia and research externships and training courses. Recruitment of women and minorities will be emphasized.


application_id: 7881468
project_number: 5R01AG020941-08
project_title: Changes in myogenic progenitor potential with age
administering_ic: NIA
award_notice_date: 2010-06-21
opportunity_number: RFA-AG-06-003
application_type: 5
activity_code: R01
ic: AG
serial_number: 020941
program_official: WILLIAMS, JOHN
project_start_date: 2002-06-01
project_end_date: 2012-06-30
study_section: ZAG1-ZIJ-2(M1)
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
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):   This project will explore a novel mechanism potentially contributing both to muscle atrophy and increased muscle lipid with age. Our work shows that in the mouse the progenitors present in muscle that are primarily responsible for postnatal muscle growth repair and maintenance activate an adipocyte-like gene program with age. The balance between myogenic and adipogenic potential appears to be regulated by Wnt signaling. In fact the constellation of Wnt ligands present and the signaling pathways activated appear to crosstalk to control muscle size and lipid content. Thus Wnt signaling may provide the mechanistic link whereby exercise influences both muscle properties. We hypothesize that Wnt signaling is altered in myogenic progenitors as a function of age contributing to impaired muscle function through loss of muscle mass and increased intramyocellular lipid following injury. In addition intermyocellular lipid increases with age and we will assess the cellular properties of myofibroblasts to test the hypothesis that changes in their potential through altered Wnt signaling may contribute to lipid accumulation surrounding myofibers. In Aim 1 we will identify the signaling pathways that account for the distinct function of WntlOb in repressing adipogenic gene expression compared to other Wnts that promote myogenic differentiation and hypertrophy and determine the role of changes in Wnt signaling in altering myogenic progenitor potential with age. Myofibroblasts will be characterized in vitro in Aim 2 to determine if adipogenic potential increases with age potentially contributing to intermyocellular lipid. Co-culture of myogenic progenitors and myofibroblasts from different aged mice will determine if age affects their interaction. In Aim 3 myogenic progenitors will be "exercised" in vitro with a Flexcell stretcher to attempt to alter adipogenic potential. Lipid accumulation and myotube size will be quantified to determine if the effects of exercise differ with age through altered signaling. Preliminary data in human myogenic progenitors suggest that age also increases their adipogenic potential and focused analyses will be translated into humans. In Aim 4 myogenic progenitors and myofibroblasts will be isolated from older compared to younger humans to characterize myogenic and adipogenic differentiation potential that will be correlated with age muscle adiposity size and strength. The effects of an exercise regimen on muscle properties in vivo will be assessed in relation to changes in myogenic progenitor potential in vitro. We will examine the underlying mechanisms involved and whether response differs with age. The long term goal of this research is to characterize changes in cell fate with age and determine their contribution to impaired muscle function in the elderly. Using this information rational new strategies for frailty prevention can be designed and tested.

project_terms:
Accounting;Adipocytes;Affect;Age;Aging;Area;Cells;Coculture Techniques;Collaborations;Data;Elderly;Equilibrium;Exercise;Gene Expression;Genes;Goals;Growth;Human;Hypertrophy;In Vitro;Injury;Intervention Studies;Knock-out;Ligands;Link;Lipids;Maintenance;Mus;Muscle;Muscle Fibers;Muscle function;Muscular Atrophy;Myoblasts;Myofibroblast;Obesity;Prevention;Property;Regimen;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Skeletal muscle structure;Testing;Transgenic Organisms;Translating;Treatment Protocols;Work;aged;design;frailty;in vitro Model;in vivo;muscle aging;muscle form;novel;postnatal;progenitor;programs;repaired;response


application_id: 7881405
project_number: 5R01DK080874-02
project_title: Regulation of the ABCG5 ABCG8 Sterol Transporter
administering_ic: NIDDK
award_notice_date: 2010-05-11
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 080874
program_official: HAFT, CAROL R
project_start_date: 2009-07-01
project_end_date: 2013-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY A
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): The purpose of this project is to determine the mechanisms by which leptin regulates the ABCG5 ABCG8 (G5G8) sterol transporter and influences cholesterol metabolism in obesity. Obesity and diabetes (diabesity) are associated with increased risk of cardiovascular and gallbladder disease elevated plasma cholesterol levels and a predilection for cholesterol synthesis rather than absorption. High-fat diets induce a virtually identical phenotype in mice. In contrast mice that lack leptin (ob/ob) or its receptor (db/db) are hyperphagic obese and diabetic yet exhibit increased cholesterol absorption reduced cholesterol synthesis decreased biliary cholesterol and resistance to cholethiasis. These observations suggest that in obesity the presence or absence of a functional leptin axis profoundly impacts cholesterol metabolism with respect to absorption synthesis and hepatobiliary transport. The central hypothesis of this proposal is that hepatic leptin signaling maintains G5G8 and prevents reductions in hepatobiliary cholesterol transport by ER stress in diabesity. The Aims are to 1) determine the role of hepatic leptin receptors on G5G8 abundance activity and cholesterol metabolism in vivo 2) determine the role of ER stress on G5G8 abundance in vivo and 3) determine the molecular mechanisms for regulation of G5G8 abundance by leptin ER stress and the ISR. Leptin receptors will be selectively deleted from liver and brain to assess the role of this signaling pathway on G5G8 and cholesterol metabolism in obesity. The effects of leptin ER stress and their interaction on G5G8 abundance will be determined in vivo and in vitro. The completion of these Aims will test our central hypothesis and elucidate the mechanisms by which the leptin axis modulates G5G8 abundance hepatobiliary lipid transport and cholesterol metabolism in diabesity. Understanding the impact of this novel pathway on cholesterol metabolism will add insight to the effects of obesity on risk factors fo cardiovascular disease. PUBLIC HEALTH RELEVANCE: The ABCG5 ABCG8 sterol transporter is the principal mechanism by which the body opposes the accumulation of dietary cholesterol and other sterols from sources such as plants and shellfish. Little is known concerning the mechanisms that regulate its abundance and activity. This proposal addresses mechanisms that are responsible for reduced abundance and activity of G5G8 in mouse models of obesity and type 2 diabetes in order to gain insight into factors that contribute to the accumulation of cholesterol in obesity.

project_terms:
Address;Adenovirus Vector;Albumins;B-Lymphocytes;Bile Acids;Bile fluid;Biliary;Brain;Cardiovascular Diseases;Cells;Cholesterol;Cholesterol Homeostasis;Diabetes Mellitus;Diamond;Diet;Dietary Cholesterol;Endoplasmic Reticulum;Enterocytes;Exhibits;Fatty acid glycerol esters;Gall Bladder Diseases;Hepatic;Hepatobiliary;Hepatocyte;Hyperlipidemia;In Vitro;Insulin;Insulin Resistance;Intestines;Leptin;Lipids;Liver;Measures;Messenger RNA;Modeling;Molecular;Molecular Chaperones;Mus;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathway interactions;Phenotype;Phytosterols;Plants;Plasma;Play;Promotor (Genetics);Proteins;Pulmonary Surfactant-Associated Protein C;Pump;Regulation;Resistance;Risk Factors;Role;Shellfish - dietary;Signal Pathway;Signal Transduction;Solid;Source;Sterols;Stress;Synapsins;Testing;Transgenes;absorption;basal insulin;bile canaliculus structure;biological adaptation to stress;cardiovascular risk factor;cholesterol absorption;db/db mouse;diabetic;endoplasmic reticulum stress;human FOXO1A protein;in vivo;insight;insulin signaling;leptin receptor;lipid transport;mouse model;novel;prevent;protein misfolding;public health relevance;receptor;recombinase;research study;response;small molecule

public_health_relevance:
7. Project NarrativeThe ABCG5 ABCG8 sterol transporter is the principal mechanism by which the body opposes theaccumulation of dietary cholesterol and other sterols from sources such as plants and shellfish. Little is knownconcerning the mechanisms that regulate its abundance and activity. This proposal addresses mechanismsthat are responsible for reduced abundance and activity of G5G8 in mouse models of obesity and type 2diabetes in order to gain insight into factors that contribute to the accumulation of cholesterol in obesity.


application_id: 7881342
project_number: 1R15NS070268-01
project_title: Behavioral and Neuroanatomical Characterization of a Novel Genetic Animal Model o
administering_ic: NINDS
award_notice_date: 2010-01-31
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: NS
serial_number: 070268
program_official: SUTHERLAND, MARGARET L
project_start_date: 2010-02-01
project_end_date: 2015-01-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 6945317
contact_pi: SCHULTHEIS, PATRICK JOHN
other_pis: Not Applicable
congressional_district: 04
department: BIOLOGY
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Mutations in ATP13A2 which encodes a lysosomal P type ATPase result in KuforRakeb syndrome an atypical form of Parkinson's disease (PD). Its yeast ortholog YPK9 has also been shown to protect against a-synuclein and manganese-induced toxicity established genetic and environmental risk factors for PD respectively. These observations suggest that ATP13A2 may play an important role in PD pathogenesis possibly through its influence on lysosomal protein degradation pathways (autophagy) and/or by functioning to sequester manganese protecting against its neurotoxic effects. We have established an animal model for this rare familial form of PD by disrupting the Atp13a2 gene in mice. In Aim 1 we will characterize the knockout mice to determine if they exhibit any of the behavioral or neuroanatomical hallmarks of PD such as motor dysfunction and loss of dopaminergic neurons in the nigrostriatal pathway. To achieve this aim wildtype (Atp13a2+/+) and Atp13a2deficient (Atp13a2-/-) mice will be subjected to an array of behavioral assays to assess motor function learning and memory and histological analyses to identify alterations in brain neuroanatomy with emphasis placed on the substantia nigra (SN) and globus pallidus (GP) regions known to be affected in sporadic PD and KuforRakeb syndrome respectively. In Aim 2 we will evaluate the sensitivity of the Atp13a2-/- mice and primary mesencephalic cultures derived from them to manganese which we anticipate may exacerbate their phenotype relative to controls. Behavioral and histological analyses on mice chronically exposed to manganese will be carried out as described in Aim 1 while cell viability and immunocytochemical assays and measurements of oxidative stress will be performed to assess the sensitivity of neurons in the primary mesencephalic cultures to the toxic effects of manganese. Data obtained from these studies may help establish an important link between genetic and environmental risk factors for PD and improve our understanding of the pathological mechanisms underlying both sporadic and genetic forms of PD.  
  
PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the second most common neurodegenerative disorder. We have created a mouse animal model to research a rare inherited form of this disease called Kufor- Rakeb syndrome. Our findings could lead to new insights into the causes of PD and its treatment.

project_terms:
ATP phosphohydrolase;Ablation;Address;Affect;Age;Animal Model;Animals;Antibodies;Anxiety;Atrophic;Autophagocytosis;Basal Ganglia;Behavior;Behavioral;Behavioral Assay;Biological Assay;Bradykinesia;Brain;Caenorhabditis elegans;Cell Count;Cell Survival;Cell physiology;Chronic;Clinical;Corpus striatum structure;Data;Degradation Pathway;Development;Disease;Dopamine;Environmental Risk Factor;Equilibrium;Exhibits;Exons;Functional disorder;Gait;Genes;Genetic;Globus Pallidus;Glutamate Decarboxylase;Homologous Gene;Human;Impaired cognition;Inclusion Bodies;Inherited;Intraperitoneal Injections;Knockout Mice;Lead;Learning;Lewy Bodies;Link;MRI Scans;Manganese;Measurement;Mediating;Memory;Mental Depression;Motor;Movement;Mus;Muscle Rigidity;Mutation;Nematoda;Nerve Degeneration;Neuroanatomy;Neurodegenerative Disorders;Neuroglia;Neurons;Orthologous Gene;Oxidative Stress;PARK9 gene;Parkinson Disease;Parkinsonian Disorders;Pathogenesis;Patients;Phenotype;Phosphorylation Site;Play;Predisposition;Proteins;Rattus;Relative (related person);Research;Rodent;Role;Saline;Staining method;Stains;Substantia nigra structure;Substrate Specificity;Symptoms;Syndrome;Testing;Toxic effect;Tremor;Tyrosine 3-Monooxygenase;Yeasts;alpha synuclein;behavior test;brain tissue;cresyl violet;design;dopaminergic neuron;enzyme activity;exposed human population;gamma-Aminobutyric Acid;improved;insight;lysosomal proteins;manganese chloride;morris water maze;neurotoxic;neurotoxicity;nigrostriatal pathway;nonhuman primate;novel;protein degradation;public health relevance

public_health_relevance:
Project Narrative:Parkinson's disease (PD) is the second most common neurodegenerative disorder. We havecreated a mouse animal model to research a rare inherited form of this disease called Kufor-Rakeb syndrome. Our findings could lead to new insights into the causes of PD and its treatment.


application_id: 7880922
project_number: 5R01ES014849-05
project_title: AHR-Protac a novel aryl hydrocarbon receptor antagonist
administering_ic: NIEHS
award_notice_date: 2010-06-18
application_type: 5
activity_code: R01
ic: ES
serial_number: 014849
program_official: DZIERLENGA, ANIKA LIN
project_start_date: 2006-08-15
project_end_date: 2012-06-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
DESCRIPTION (provided by applicant): The broad long term goals of this proposal are to use a novel class of antagonists of the aryl hydrocarbon receptor (AHR) AHR-Protacs developed herein as 1) a research tool to delineate the mechanisms by which activation of the AHR pathway by environmental agents leads to carcinogenesis in the human population and identify roles of the AHR in other disease processes and 2) a therapeutic agent to treat cancers diabetes and cardiovascular diseases. Exposures to environmental factors such as benzo[a]pyrene and 2378 tetrachlorodibenzo-p-dioxin (TCDD) are thought to play important roles in the development of human cancers. While these agents are known to exert many of their carcinogenic actions via activation of the AHR the mechanisms by which the AHR elicits the key events are unknown. Further it has not yet been established whether targeting the AHR would be an effective chemopreventive approach. Finally emerging evidence implicates a role for the AHR in not only cancer but also diabetes and cardiovascular diseases. The immediate goals of the current proposal are to optimize and characterize novel AHR antagonists some of which have already been developed in our laboratories as appropriate AHR antagonists. Specific Aims: (1) Synthesis of optimum AHR Protacs. (2) Determine that the optimum AHR Protac molecule(s) inhibits AHR signaling in cultured cells with high efficacy. (3) Determine whether the optimum AHR Protac(s) inhibits the ability of TCDD to alter cell cycle apoptosis and senescence. (4) Determine whether the optimum AHR Protac(s) alters the AHR pathway with high specificity. The work proposed herein will develop a novel research tool that can be used to identify how inappropriate activation of the AHR by environmental carcinogens leads to human cancers and to understand the role of the AHR in normal biological processes. In addition this work will set the stage for the development of drugs that target the AHR and may be clinically useful not only as agents that may prevent cancers but may also be effective in the treatment of diabetes and cardiovascular diseases.

project_terms:
Address;Affinity Chromatography;Agonist;Apigenin;Apoptosis;Aryl Hydrocarbon Receptor;Benzo(a)pyrene;Biological;Biological Factors;Biological Process;Biotin;Cardiovascular Diseases;Cell Cycle;Cells;Chemopreventive Agent;Coupled;Cultured Cells;DNA Binding;Development;Diabetes Mellitus;Dioxins;Disease;Drug Delivery Systems;Environmental Carcinogens;Environmental Pollution;Environmental Risk Factor;Event;Exhibits;Exposure to;G1 Arrest;Genetic Transcription;Goals;Human;Human Development;Kaempferols;Label;Laboratories;Ligands;Malignant Neoplasms;Pathway interactions;Pharmaceutical Preparations;Play;Population;Process;Protac;Proteins;Receptor Signaling;Recruitment Activity;Reporter;Research;Role;Signal Pathway;Small Interfering RNA;Specificity;Staging;Technology;Therapeutic Agents;Tumor Initiators;Tumor Promoters;Work;base;carcinogenesis;design;environmental agent;kaempferol;novel;novel strategies;prevent;receptor;receptor expression;research study;senescence;small molecule;stem;tool


application_id: 7880633
project_number: 5R01CA138688-02
project_title: Convergence of MicroRNAs and p53 Signaling in Multiple Myeloma: Environmental Co
administering_ic: NCI
award_notice_date: 2010-04-22
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 138688
program_official: JOHNSON, RONALD L
project_start_date: 2009-07-01
project_end_date: 2014-04-30
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 8146758
contact_pi: LI, YONG
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
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): Multiple myeloma (MM) is one of the most common hematological neoplasms. It constitutes about 1% of human cancers and 2% of all cancer deaths. Polycylic aromatic hydrocarbons such as 2378- tetrachlorodibenzo--dioxin (TCDD) have been closely correlated to MM by epidemiologic studies yet the biologic mechanisms of a causal relationship between TCDD exposure and MM have not been well understood. One of the unique features of MM compared to other cancers is the extremely low genetic mutation rate of the tumor protein p53 (TP53) gene. TP53 encodes the p53 tumor suppressor guardian of the human genome. Genomic instability (chromosome translocation aneuploidy and gene mutation) is widely observed in MM and reveals that the function of p53 as the guardian of the human genome is compromised in MM. We explored the molecular mechanisms of p53 inactivation in MM by a new class of noncoding small RNAs microRNAs (miRNAs) as recent reports have demonstrated that some miRNAs such as miR-34 are important players in the p53 tumor suppressor network. We hypothesize that miRNAs negatively regulate the human TP53 gene in MM. We propose three aims for this project: first we will identify miRNAs that target the human TP53 gene by a combination of mutagenesis reporter expression and immunoblotting analyses; second we will assess the pathological significance of miRNA:TP53 interactions in MM cell lines and primary MM cells by expression profiling and miRNA inhibition assays; third we will determine whether dioxin modulates p53 signaling by upregulating miRNA expression. A novel p53 inactivation mechanism by an miRNA that is upregulated by dioxin will lead to unique targets for diagnostic markers and therapeutic interventions in MM patients as well as provide a better understanding of the biological interactions between dioxin exposure and MM tumorigenesis. PUBLIC HEALTH RELEVANCE: TP53 gene alterations are rare and late events in multiple myeloma (MM) the second most common hematological malignancy constituting about 1% of all human cancers. It is critical to explore whether there are unique mechanisms that inactivate wild-type TP53 function as an early and original molecular event in MM development. The proposed research plan is to test the hypothesis that TP53 is negatively regulated by microRNAs (miRNAs) a class of newly discovered small noncoding RNAs to define whether miRNA dysregulation contributes to tumorigenesis prior to TP53 gene alterations and to determine whether dioxin modulates p53 signaling through upregulating miRNA expression.

project_terms:
101 Mouse;ARNT gene;Aneuploidy;Antisense RNA;Apoptosis;Apoptotic;Aromatic Hydrocarbons;Aromatic Polycyclic Hydrocarbons;Aryl Hydrocarbon Receptor;Benzo(a)pyrene;Binding Sites;Biological;Biological Assay;Biological Process;Bone Marrow;CDKN2A gene;Cell Aging;Cell Cycle Arrest;Cell Death;Cell Line;Cells;Cellular Assay;Cessation of life;Characteristics;Chromosomal translocation;Clinical;Code;Collaborations;Computing Methodologies;Cytoplasm;Development;Diagnosis;Diagnostic;Diagnostic Neoplasm Staging;Dioxins;Double Minutes;Drug Delivery Systems;Elements;Environmental Pollution;Environmental Risk Factor;Epidemiologic Studies;Epigenetic Process;Etiology;Event;Exposure to;FDA approved;Gene Expression;Gene Library;Gene Mutation;Gene Targeting;Genes;Genome;Genomic Instability;Hematologic Neoplasms;Human;Human Genome;Immunoblotting;Immunoglobulins;Incidence;Infiltration;Laboratories;Lead;Little's Disease;MDM2 Gene Amplification;Malignant Neoplasms;Mediating;Messenger RNA;Methods;MicroRNAs;Molecular;Molecular Profiling;Monitor;Multiple Myeloma;Mus;Mutagenesis;Mutate;Mutation;Neoplasms;Neoplastic Plasma Cell;Nucleotides;Oncogene Activation;Onset of illness;Pathogenesis;Patients;Pattern;Pharmaceutical Preparations;Physiological;Plasma Cells;Process;Promotor (Genetics);Protein p53;Proteins;RNA;Regulation;Reporter;Reporting;Research;Role;Sampling;Signal Transduction;Small RNA;Specimen;TP53 gene;Testing;Therapeutic Intervention;Time;Tumor stage;Tumor-Suppressor Gene Inactivation;Universities;Untranslated RNA;Untranslated Regions;Viral Proteins;Wisconsin;antiangiogenesis therapy;base;biomarker;clinically significant;mutant;novel;overexpression;p14ARF Protein;prevent;prognostic;public health relevance;research study;response;stressor;tool;tumor;tumorigenesis;vector

public_health_relevance:
Project NarrativeTP53 gene alterations are rare and late events in multiple myeloma (MM) the second most commonhematological malignancy constituting about 1% of all human cancers. It is critical to explore whether thereare unique mechanisms that inactivate wild-type TP53 function as an early and original molecular event in MMdevelopment. The proposed research plan is to test the hypothesis that TP53 is negatively regulated bymicroRNAs (miRNAs) a class of newly discovered small noncoding RNAs to define whether miRNAdysregulation contributes to tumorigenesis prior to TP53 gene alterations and to determine whether dioxinmodulates p53 signaling through upregulating miRNA expression.


application_id: 7879520
project_number: 5R13CA124224-05
project_title: Louisville Breast Cancer Update
administering_ic: NCI
award_notice_date: 2010-07-12
opportunity_number: PA-06-041
application_type: 5
activity_code: R13
ic: CA
serial_number: 124224
program_official: SONG, MIN-KYUNG H
project_start_date: 2006-09-01
project_end_date: 2011-07-31
study_section: ZCA1-GRB-T(M1)
contact_pi_person_id: 7874100
contact_pi: CHAGPAR, ANEES B
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
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 purpose of the Louisville Breast Cancer Update is to provide a high quality forum for the dissemination of advances in the state-of-the-art multidisciplinary management of breast cancer and to allow for an exchange of ideas regarding controversial issues regarding care of breast cancer patients. Lectures from some of the most prominent breast cancer researchers and clinicians will be presented covering all aspects of breast cancer care. This year topics to be covered will include: Indications utility and challenges of MRI; minimally invasive mastectomy; Innovations in reconstruction; Advances in systemic chemotherapy; Hormones in breast cancer: to replace or inhibit?; Targeted therapy for breast cancer; Genomics in the management of breast cancer; Advances in radiation therapy: should we be doing more or less?; Prevention genetics and high risk breast cancer and Supportive Care Issues. In addition this meeting will be expanded to facilitate the interaction between basic scientists and clinicians with a scientific poster session that will promote fruitful collaborations and a common understanding of progress in the breast cancer arena from bench to bedside. The meeting will therefore further the NCI's mission for the alleviation of suffering and death due to cancer by providing a forum for the dissemination of advances in the multidisciplinary care of patients with breast cancer and the building of collaborations that will promote further research in this area. This annual event is the only one of its kind in Kentucky and provides an important resource for education of clinicians scientists and advocates.

project_terms:
Advocate;Area;Arts;Cancer Patient;Caring;Cessation of life;Collaborations;Educational aspects;Event;Genetic;Genomics;Hormones;Kentucky;Magnetic Resonance Imaging;Malignant Neoplasms;Mastectomy;Mission;Patient Care;Prevention;Radiation therapy;Research;Research Personnel;Resources;Scientist;Supportive care;Update;bench to bedside;cancer care;chemotherapy;high risk;innovation;lectures;malignant breast neoplasm;meetings;minimally invasive;multidisciplinary;posters;reconstruction


application_id: 7877958
project_number: 5R01AG028925-05
project_title: INTEGRATED STUDY OF MUSCULOSKELETAL LOSS AND RESTORATION
administering_ic: NIA
award_notice_date: 2010-06-21
opportunity_number: PA-03-147
application_type: 5
activity_code: R01
ic: AG
serial_number: 028925
program_official: WILLIAMS, JOHN
project_start_date: 2006-09-15
project_end_date: 2013-04-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
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): Mechanisms controlling musculoskeletal recovery following disuse are poorly understood. However there is evidence that the restoration of lost tissue is impaired with aging. Precursor cell function in both muscle and bone is altered with advancing age which may contribute to the decreased recovery. The goal of this proposal is to investigate the role of tissue-specific precursor cells during the recovery from bone loss and muscle atrophy in response to hind-limb suspension (HS) in rats and to determine whether there are age- associated differences in this process. We hypothesize that changes in the function of tissue-specific precursor cells impair the restoration of musculoskeletal mass with advancing age. The strength of our approach is that both muscle and skeletal components will be studied in the same animals facilitating evaluation of the interaction between the two systems and the integration of common mechanisms. In Aim 1 we will investigate whether advancing age decreases the capacity to recover (by reambulation) the musculoskeletal atrophy induced by HS. The temporal correlation between loss of muscle and bone and their capacity for restoration will be investigated. Aim 2 addresses whether the underlying mechanisms of precursor cell function and apoptosis in bone and muscle are changed with aging and contribute to the impaired recovery from lost tissue in vivo. In Aim 3 bone marrow stem cells and myoblasts will be isolated and proliferation differentiation and apoptotic responses in vitro determined to investigate whether age- associated changes in these processes contribute to atrophy and impaired restoration of musculoskeletal mass. Our preliminary data suggest an age-dependent role for altered BMP signaling that may account for diminished restorative capacity in bone. Whether BMP is a common target underlying the mechanistic basis of bone and muscle regulation during aging and disuse will be determined. Finally in Aim 4 we will investigate in vitro and in vivo whether changes in the insulin-like growth factor (IGF)-1 pathway are involved in the impaired restoration of musculoskeletal mass with aging. Together these studies will provide important insight into the cellular mechanisms underlying the impaired ability of older animals to recover musculoskeletal integrity after disuse. Our proven integrative approach for studying muscle and bone will enable us to elucidate common mechanisms underlying the responsiveness of the musculoskeletal system during aging. Relevance to public health: Advancing age is associated with a loss of muscle as well as bone mass and it is unknown whether the musculoskeletal system in older individuals differs in its restorative capacity after periods of disuse. In this study we will identify common mechanisms underlying age-related changes in progenitor cell function. Identifying these common pathways influencing muscle and bone integrity could lead to putative targets for pharmacologic or therapeutic interventions.

project_terms:
Accounting;Address;Age;Aging;Animals;Apoptosis;Apoptotic;Atrophic;Bed rest;Bone Density;Bone Marrow;Bone Marrow Stem Cell;Cell Nucleus;Cell physiology;Cells;Data;Disease;Elderly;Evaluation;Event;Face;Goals;In Vitro;Individual;Insulin-Like Growth Factor I;Lead;Life;Limb structure;Longevity;Maintenance;Marrow;Mechanics;Molecular;Muscle;Muscle Fibers;Muscular Atrophy;Musculoskeletal;Musculoskeletal System;Myoblasts;NIH Program Announcements;Nuclear;Operative Surgical Procedures;Osteocytes;Osteopenia;Pathway interactions;Process;Rattus;Recovery;Regulation;Role;Signal Transduction;Skeletal muscle structure;Stem cells;Suspension substance;Suspensions;Systems Integration;Testing;Therapeutic Intervention;Time;Tissues;Workload;age related;base;bone;bone loss;bone mass;in vivo;insight;juvenile animal;muscle form;osteoblast differentiation;paracrine;precursor cell;public health medicine (field);response;restoration;sarcopenia;satellite cell


application_id: 7876986
project_number: 5R21CA133668-02
project_title: Stable isotopomer analysis of anabolic metabolic pathways in breast cancer
administering_ic: NCI
award_notice_date: 2010-06-03
opportunity_number: PA-07-302
application_type: 5
activity_code: R21
ic: CA
serial_number: 133668
program_official: SPALHOLZ, BARBARA A
project_start_date: 2009-07-01
project_end_date: 2012-06-30
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
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): Despite the numerous advances in technology and screening breast cancer remains the major form of human cancers (lifetime risk ca. 1/8).  A neglected aspect of tumorigenesis is the metabolic profile of cells which expresses the biochemical phenotype.  Transformed cells differ from their normal counterparts by loss of critical regulatory functions that lead to immortalization avoidance of apoptosis and deregulated cell cycling.  A dividing cell must double its contents during each cycle requiring intake of materials both for biosynthesis and to provide the energy to drive endergonic anabolic reactions.  Thus cancer cells must increase the activity of metabolic pathways for energy production and anabolism.  Cancer cells of different origin should display metabolism characteristic of the cell type and reflect specific aspects of proliferation and how these depend on the external conditions such as the supply of nutrients and oxygen.  We propose to determine the relative importance of specific cancer-relevant metabolic pathways in the development and progression of breast cancer cells (four lines) both in cell culture and in an orthotopic mouse tumor model (xenografts) using stable isotope assisted metabolomics by NMR and MS as follows.  Aim 1. To determine the relative importance of energy producing pathways and anabolic metabolism by quantitative isotopomer analysis of normal and cancerous human breast epithelial cells in culture in response to hypoxia and specific nutrients.  The precursors ([U-13C]-glucose [13C-1] and [13C-2] glucose) and 13C/15N glutamine can differentiate relative fluxes through glycolysis pentose phosphate pathways citric acid cycle and major anaplerotic reactions amino acid metabolism nucleobase and phospholipid biosynthesis.  Relative fluxes through these major pathways in non-estrogen-sensitive MDAMB231 and estrogen sensitive ZR-75-1 and MCF-7 cells will be compared with normal human mammary epithelial cells (HMEC).  Aim 2. To determine the extent that the specific pathway activities identified in cell culture are present in actual tumors in a xenograft mouse model.  Female nude mice bearing mammary fat pad tumors deriving from non MDAMB231 and ZR-75-1 cells are given 13C glucose or 13C/15N glutamine i.v. and the tumors excised after sufficient time has elapsed for metabolism to occur.  Plasma is analyzed to monitor uptake and redistribution of labeled precursors.  Metabolites are extracted and analyzed by the same techniques as in Aim 1.  The comparison of the tumor model with cell culture shows how the tumor environment and tissue interactions determine the relative importance of different pathways to breast tumor progression.  The biochemical information will be used to interpret the metabolic profiles of human breast cancers.  The development of these approaches will provide basic biochemical information about breast cancer and is essential for the design of future studies with human subjects with the goal of improved diagnosis of early stage tumors.  PUBLIC HEALTH RELEVANCE: Despite the numerous advances in technology and screening breast cancer remains the major form of human cancers (lifetime risk ca. 1/8).  However although oncogenes such as Myc and Ras or tumor suppressors such as p53 are frequently upregulated in cancers the precise roles of these factors in disease initiation and progression is not completely clear.  A deeper understanding of the biochemical phenotype of cancerous cells and their normal counterparts under defined conditions is an essential counterpart to genomics analyses of cancer cells.  We are developing the technology to measure the activity of biochemical pathways in cancer cells that ultimately can be applied to human tumors in a clinical setting.  The comparison of the in vivo tumor model with cell culture will show how the tumor environment and tissue interactions may determine the relative importance of different metabolic pathways to breast tumor progression.  This fundamental knowledge of tumor biochemistry then provides a rich source of hypotheses about tumor progression that can be tested directly in actual breast cancer tissue.  Application of this approach to a clinical setting will set the stage for identifying sets of markers for early diagnosis prognosis and ultimately drug responses.

project_terms:
Accounting;Aerobic;Amino Acids;Anabolism;Apoptosis;Biochemical;Biochemical Pathway;Biochemistry;Biomass;Breast;Breast Cancer Cell;Breast Cancer Detection;Cancerous;Cell Culture Techniques;Cell Cycle;Cell Proliferation;Cells;Characteristics;Citric Acid Cycle;Clinical;Data;Development;Diagnostic Neoplasm Staging;Disease;Early Diagnosis;Environment;Epithelial Cells;Estrogens;Fatty acid glycerol esters;Female;Future;Genomics;Genotype;Glucose;Glutamine;Glycolysis;Goals;Human;Hypoxia;Intake;Knowledge;Label;Laboratories;Lead;Lifetime Risk;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Mammary gland;Mass Spectrum Analysis;Measures;Messenger RNA;Metabolic;Metabolic Pathway;Metabolism;Modeling;Monitor;Mus;Nude Mice;Nutrient;Oncogenes;Oxygen;Pathway interactions;Pentosephosphate Pathway;Pharmaceutical Preparations;Phenotype;Phospholipid Metabolism;Phospholipids;Plasma;Production;Proteins;Reaction;Regulation;Relative (related person);Role;Sampling;Solid Neoplasm;Source;Staging;System;TP53 gene;Techniques;Technology;Testing;Time;Tissues;Tracer;Tumor Suppressor Proteins;Tumor stage;Tumor-Derived;Warburg Effect;Xenograft Model;Xenograft procedure;aminoacid biosynthesis;cancer cell;cell transformation;cell type;design;human subject;improved;in vivo;interest;malignant breast neoplasm;metabolomics;mouse model;neglect;nucleobase;outcome forecast;public health relevance;response;stable isotope;tumor;tumor progression;tumorigenesis;uptake

public_health_relevance:
Despite the numerous advances in technology and screening breast cancer remains the major form of humancancers (lifetime risk ca. 1/8). However although oncogenes such as Myc and Ras or tumor suppressorssuch as p53 are frequently upregulated in cancers the precise roles of these factors in disease initiation andprogression is not completely clear. A deeper understanding of the biochemical phenotype of cancerous cellsand their normal counterparts under defined conditions is an essential counterpart to genomics analyses ofcancer cells. We are developing the technology to measure the activity of biochemical pathways in cancercells that ultimately can be applied to human tumors in a clinical setting. The comparison of the in vivo tumormodel with cell culture will show how the tumor environment and tissue interactions may determine therelative importance of different metabolic pathways to breast tumor progression. This fundamental knowledgeof tumor biochemistry then provides a rich source of hypotheses about tumor progression that can be testeddirectly in actual breast cancer tissue. Application of this approach to a clinical setting will set the stage foridentifying sets of markers for early diagnosis prognosis and ultimately drug responses.


application_id: 7876889
project_number: 5R25RR023304-05
project_title: "TRY-IT" Translating Research to Youth through Information Technology
administering_ic: NCRR
award_notice_date: 2010-06-25
opportunity_number: PAR-06-080
application_type: 5
activity_code: R25
ic: RR
serial_number: 023304
program_official: BECK, LAWRENCE A
project_start_date: 2006-09-15
project_end_date: 2014-06-30
study_section: ZRR1-SEPA-9(01)
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:
DESCRIPTION (provided by applicant): This Science Education (SEPA) project called "TRY-IT" (Translating Research to Youth through Information Technology) is submitted by the University of Kentucky with the Explorium Science Museum to increase minority and underrepresented student knowledge and participation in biomedical science careers as well as interest in clinical research trials. The project addresses the limited opportunities for disadvantaged middle school and minority youth to learn about careers in biomedical research and clinical trials because the number of underrepresented minority students who enter biomedical sciences and go on to pursue graduate education is very small. This project focuses on helping students apply technology to better understand biomedical science. This novel approach uses interactive 3-D visualization as a "hook" or an "engagement point" so middle school students can progress to learn more about biomedical science technology and human health. This is a combined Phase I development and a Phase II dissemination application. During Phase I middle school students their teachers school counselors and parents will participate in a two-year year round science-enrichment program to increase the likelihood that participating students will consider careers in biomedical sciences. Project teams will work with the Explorium Science Museum to create traveling exhibits involving interactive 3-D models. During Phase II the curriculum and the exhibits that are developed by the student/teacher/researcher project teams will be disseminated to all middle school students in Kentucky and made available online. The specific project aims are to: (1) Increase the interest and knowledge of minority and underrepresented middle school students ages 11 to 15 in biomedical science clinical trials and scientific uses of technology; (2) Expand the biomedical science technology skills and biomedical science career knowledge of middle school teachers and counselors serving minority and underrepresented students; (3) Evaluate changes in student interest knowledge skills and changes in career paths in biomedical science; and (4) Design and distribute the "TRY-IT" curriculum which includes a technology-rich exhibit for K-12 students.

project_terms:
3-Dimensional;Academy;Address;Age;Award;Awareness;Behavioral Sciences;Biomedical Research;Biomedical Technology;Clinical Research;Clinical Trials;Commit;Communities;County;Development;Disadvantaged;Drug abuse;Educational Curriculum;Educational aspects;Educational workshop;Exhibits;Family;Future;Gambling;Gender;Goals;Graduate Education;Hand;Health;Human;Human Biology;Imagery;Information Technology;Institutes;Institution;Instruction;Kentucky;Knowledge;Learning;Life Style;Mentors;Minority;Modeling;Museums;National Center for Research Resources;Parents;Participant;Pharmaceutical Preparations;Phase;Play;Professional counselor;Research;Research Personnel;Role;Rural;School Teachers;Schools;Science;Science Enrichment;Scientist;Students;Technology;Testing;Translating;Travel;Underrepresented Minority;United States National Institutes of Health;Universities;Woman;Work;Youth;alcohol research;boys;career;design;experience;girls;interest;literacy;middle school;novel;novel strategies;programs;research study;rural area;science education;skills;success;teacher


application_id: 7874552
project_number: 5R01MH074865-04
project_title: BE-ACTIV: Treating Depression in Nursing Homes
administering_ic: NIMH
award_notice_date: 2010-07-13
application_type: 5
activity_code: R01
ic: MH
serial_number: 074865
program_official: ROWLAND, LAURA
project_start_date: 2007-07-14
project_end_date: 2012-06-30
study_section: Interventions Committee for Disorders Related to Schizophrenia, Late Life, or Personality[ITSP]
contact_pi_person_id: 1908020
contact_pi: MEEKS, SUZANNE
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this proposal is to test the efficacy of a behavioral intervention for depression in nursing homes. The program BE-ACTIV has been adapted and piloted in nursing homes and shows promise of reducing depression in residents with major and minor depression. The intervention is conceptually based on Lewinsohn's behavioral theory of depression and derived from Teri's effective outpatient intervention for elders with dementia. It involves collaboration between a mental health therapist and nursing home Activities Department staff and is tailored to the individual resident. The goal is to increase opportunities for pleasant events thus increasing activity and positive affect. There are 2 specific aims: (1) using a randomized controlled two-group design to compare outcomes for depressed residents receiving the BE-ACTIV program with those receiving treatment as usual in their nursing homes; and (2) to evaluate the treatment mechanisms including staff attention increased activity levels and increased positive affect related to improvement following participation in BE-ACTIV. The latter aim employs both within-subject process measures and between-subject comparisons. Measures include diagnostic evaluation depression and mood rating scales general functioning observed affect and activity participation behavior problems resident satisfaction and staff burden. Analyses will make use of random effects modeling to analyze within- and between-subject variability in intervention process and treatment response.   
Public Health Relevance: Nursing home residents are at a significantly higher risk for depression than community-residing elders; up to 50% of nursing home residents are affected by significant depressive symptoms. The health and cognitive multiple comorbidity of this population makes treatment and treatment research extremely challenging. Although we have a good understanding of the epidemiology and manifestations of depression in late life and are beginning to apply effective treatments to some groups of elders the benefits of the past decade of research have yet to reach these frailest elders.

project_terms:
Affect;Aftercare;Attention;Behavior Therapy;Behavioral;Cognitive;Collaborations;Communities;Comorbidity;Data;Dementia;Depressed mood;Depressive disorder;Diagnosis;Diagnostic;Discipline of Nursing;Elderly;Epidemiology;Evaluation;Event;Face;Foundations;Goals;Health;Individual;Institution;Intervention;Interview;Interviewer;Link;Manuals;Measures;Mediating;Mental Depression;Mental Health;Modeling;Moods;Nurses;Nursing Homes;Outcome;Outcome Measure;Outpatients;Participant;Patient Self-Report;Phase;Population;Positive Reinforcements;Problem behavior;Process;Process Measure;Randomized;Recovery;Research;Research Personnel;Risk;Social Functioning;Structure;Symptoms;Testing;Theoretical model;base;blind;depressive symptoms;design;effective therapy;efficacy testing;follow-up;health practice;high risk;intervention program;member;minor depressive disorder;programs;public health medicine (field);public health relevance;satisfaction;social;symptomatic improvement;theories;treatment as usual;treatment response


application_id: 7873628
project_number: 2T35DK072923-06
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2011-04-07
opportunity_number: PA-08-227
application_type: 2
activity_code: T35
ic: DK
serial_number: 072923
program_official: PODSKALNY, JUDITH M,
project_start_date: 2006-05-01
project_end_date: 2016-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
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 is a competing renewal of NIH 5 T35 DK072923 which was originally funded for five years with 6 students supported/year. The principal objectives of the Summer Endocrine Research Training Program are to provide research experience for medical students and to stimulate interest among medical students in becoming clinical research scientists. Trainees engage in research activities with faculty members and participate in projects that are germane to the field of endocrinology and the health concerns of this country. Over the past 3 years we have trained 18 second year medical students who participated in our "Summer Endocrine Research Training Program" research programs in Endocrinology Metabolism and Diabetes at University of Louisville School of Medicine and as this application is submitted 6 new second year medical students will begin their summer research in this program. Approximately 25% of our trainees are members of minority populations and 1/3rd of trainees are female. Our program includes didactic instruction ("Summer Endocrine Research Training Seminar Series" and "Bench-to-Bedside: Introduction to Clinical Research") as well as a hands-on-research experience under the direction of a team of experienced basic and clinical research scientists centered on a core of NIDDK-funded investigators and collaborating faculty. Trainees also attend Endocrine-specific seminars and journal clubs in basic and clinical research. The present application addressses 2 Specific Aims: Aim 1: To provide hands-on training in basic and clinical Endocrine-based research to medical students in a structured mentored environment. Aim 2: To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical Endocrine-based research. The T35 competing renewal funding will provide stipends for a 10-week summer program for 8-10 second year medical students. Our current T35 grant funds 6 students/year. Given the increase in training faculty mentors and NIDDK-funded research at the University of Louisville School of Medicine documented within the text we request funds to increase to 8 students/year in years 6 and 7 (Yr. one and two of the next funding period) 9 in years 8 and 9 (Yr. three and four of the next funding period and 10 in year 10 (Yr. five of the next funding period).   
  
PUBLIC HEALTH RELEVANCE: This competing renewal T35 application directly addresses the NIH's goal of ensuring that a diverse pool of highly trained scientists are available in the field of Endocrinology to address the Nation's biomedical and clinical research needs.

project_terms:
Basic Science;Clinical;Clinical Research;Country;Diabetes Mellitus;Endocrine;Endocrinology;Environment;Faculty;Female;Funding;Grant;Health;Instruction;Journals;Medical Students;Mentors;Minority;National Institute of Diabetes and Digestive and Kidney Diseases;Population;Research;Research Activity;Research Personnel;Research Training;Scientist;Series;Structure;Students;Text;Training;Training Programs;United States National Institutes of Health;Universities;base;bench to bedside;experience;interest;medical schools;member;programs;skills

public_health_relevance:
This competing renewal T35 application directly addresses the NIH's goal of ensuring that a diverse pool of highly trained scientists are available in the field of Endocrinology to address the Nation's biomedical and clinical research needs.


application_id: 7873051
project_number: 5P20RR018733-08
project_title: Molecular Targets COBRE
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
program_official: CANTO, MARIA TERESA
project_start_date: 2003-09-01
project_end_date: 2013-06-30
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
budget_start_date: 2010-07-01
project_abstract:
DESCRIPTION (provided by applicant): The University of Louisville Molecular Targets Center of Biomedical Research Excellence (MT-COBRE) is focused on identification of novel molecular targets for cancer therapy emphasizing structural biologic approaches for development of novel therapeutics. The overall objective of the MT-COBRE is to recruit and ensure the success of junior investigators who are members of the Molecular Targets Program at the UofL's Brown Cancer Center. We have made considerable progress towards accomplishment of the goals of the original application during the first five year funding period. Four of the original five COBRE scientists have received NIH R01 funding the fifth was encouraged to pursue other directions. Five outstanding new scientists have taken their places three of whom have NIH R01 applications under review or being revised for resubmission. We have been quite fortunate during the initial funding period to have retained all of the MT-COBRE faculty. We have leveraged the MT-COBRE support to create a set of effective Core Facilities which have significantly enhanced the productivity of the MT-COBRE investigators and other Brown Cancer Center scientists. The renewal application has added a new Core the Biophysics Core Facility and deleted a Core which was underutilized the Proteomics Core Facility. The specific aims of the proposal are to: 1. develop successful independent research careers for each of the principal investigators that will lead to independent R01 grants. 2. develop core facilities that will enhance the research capability of the principal investigators and the other members of the MT program. 3. continue to develop the Molecular Targets Program as a cohesive research program which will enhance collaborative research projects and funding opportunities. 4. develop a nationally and internationally recognized program which will attract the very best graduate students postdoctoral fellows and additional faculty. 5. make discoveries leading to new and more effective treatments for patients with cancer. During the next funding period the MT-COBRE will utilize focused recruitment to enhance the scope of the program. Funding of this renewal application is critically important to allow the program to achieve its potential. Based on its current faculty and projected growth during the next funding period this program is poised to become one of the nation's premiere cancer drug development programs.

project_terms:
Antineoplastic Agents;Biophysics;Cancer Center;Centers of Research Excellence;Core Facility;Development;Ensure;Faculty;Funding;Funding Opportunities;Goals;Grant;Growth;Lead;Malignant Neoplasms;Mentors;Molecular Target;Patients;Postdoctoral Fellow;Principal Investigator;Productivity;Proteomics;Recruitment Activity;Research;Research Personnel;Research Project Grants;Scientist;United States National Institutes of Health;Universities;base;cancer therapy;career;drug development;effective therapy;graduate student;member;novel;novel therapeutics;programs;success


application_id: 7873036
project_number: 5R03AI079442-02
project_title: MHC-Ib restricted T cell responses against Listeria monocytogenes
administering_ic: NIAID
award_notice_date: 2010-04-21
opportunity_number: PA-06-180
application_type: 5
activity_code: R03
ic: AI
serial_number: 079442
program_official: MILLS, MELODY
project_start_date: 2009-06-18
project_end_date: 2012-05-31
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
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): 1 Listeria monocytogenes (Lm) is a category B priority pathogen that causes outbreaks of 2 foodborne illness with a high incidence of morbidity and mortality. To achieve sterilizing 3 immunity against Lm CD8+ T cells must recognize antigens bound to MHC-I proteins on the 4 surface of infected cells an event that results in activation of the T cells and acquisition of 5 protective effector functions. Classical MHC-I proteins (MHC-Ia) have been studied for 6 decades however comparatively little is known about most of the non-classical MHC-I proteins 7 (MHC-Ib). We developed a MHC-Ia deficient mouse model of Lm infection to study the role of 8 MHC-Ib restricted T cells in the clearance of intracellular bacterial pathogens. Our central 9 hypothesis is that Lm-immune mice contain memory CD8+ T cells that recognize novel MHC-Ib 10 proteins and that these T cells play a significant role in the clearance of secondary Lm infection. 11 In preliminary studies we showed that CD8+ T cells that recognize antigen in the context of a 12 novel (not M3) MHC-Ib protein are activated during Lm infection. We have identified nine 13 murine MHC-Ib genes as likely candidates to express proteins that could serve as antigen 14 presenting molecules during infection. In this application we propose to: 1) develop a panel of 15 human macrophage-like cells transfected with each of the nine candidate MHC-Ib genes and 2) 16 use the MHC-Ib transfectants to determine how many different MHC-Ib proteins are capable of 17 presenting antigen to T cells during Lm infection. These studies will help to define the role of 18 MHC-Ib restricted T cells in protective immune responses against Lm and may facilitate the 19 identification of new classes of antigens for all intracellular bacterial pathogens. Since most 20 MHC-Ib proteins are non-polymorphic antigens that bind to MHC-Ib proteins are likely to be 21 recognized by most if not all of the individuals in a given population. This makes MHC-Ib 22 antigens particularly attractive candidates for inclusion in vaccines designed to protect against 23 infection with intracellular bacterial pathogens. PUBLIC HEALTH RELEVANCE: One of the significant hurdles faced in trying to design vaccines to protect against infection with bacteria that can survive inside host cells is the identification of antigens that will be recognized by all individuals regardless of their blood type (MHC haplotype). In this study we will characterize a subset of T cells that recognize antigens derived from Listeria monocytogenes bound to MHC-Ib proteins a class of proteins that is non- polymorphic (displays little variation among individuals) in both mice and humans. These studies have the potential to lead to new therapeutic strategies to protect against infections with a variety of intracellular bacteria including prevalent human pathogens such as Mycobacteria tuberculosis and Chlamydia trachomatis.

project_terms:
Antigenic Specificity;Antigens;Attention;Bacteria;Bacterial Infections;Binding (Molecular Function);Blood typing procedure;CD8B1 gene;Categories;Cell Line;Cell surface;Cells;Chlamydia;Chlamydia trachomatis;Disease Outbreaks;Event;Genes;Genetic Polymorphism;Genus Mycobacterium;Haplotypes;Harvest;Human;Immune;Immune response;Immunity;Incidence;Individual;Infection;Lead;Lipids;Listeria monocytogenes;Mediating;Mediator of activation protein;Memory;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Mycobacterium tuberculosis;Organism;Peptides;Play;Population;Proliferating;Proteins;Qa-1 Antigen;Reporting;Role;Salmonella;Splenocyte;Surface;T cell response;T memory cell;T-Cell Activation;T-Lymphocyte;T-Lymphocyte Subsets;Time;Vaccine Design;Variant;adaptive immunity;antigen binding;design;foodborne;foodborne illness;macrophage;mouse model;novel;novel therapeutics;pathogen;public health relevance;research study;response

public_health_relevance:
Project Narrative:One of the significant hurdles faced in trying to design vaccines to protect against infection with bacteria thatcan survive inside host cells is the identification of antigens that will be recognized by all individuals regardlessof their blood type (MHC haplotype). In this study we will characterize a subset of T cells that recognizeantigens derived from Listeria monocytogenes bound to MHC-Ib proteins a class of proteins that is non-polymorphic (displays little variation among individuals) in both mice and humans. These studies have thepotential to lead to new therapeutic strategies to protect against infections with a variety of intracellularbacteria including prevalent human pathogens such as Mycobacteria tuberculosis and Chlamydia trachomatis.


application_id: 7872348
project_number: 3R01NS040334-08S2
project_title: TRANSGENETIC STUDIES OF PRION DISEASE IN CERVIDS
administering_ic: NINDS
award_notice_date: 2009-08-28
application_type: 3
activity_code: R01
ic: NS
serial_number: 040334
suffix: S2
program_official: DALEY, WILLIAM PATRICK
project_start_date: 2000-08-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZRG1-CNBT(01)]
contact_pi_person_id: 7875112
contact_pi: TELLING, GLENN C
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):  Our broad long-term objective is to address the mechanisms by which species barriers and strain specificities control the pathogenesis and transmission of chronic wasting disease (CWD) a contagious disease of deer and elk belonging to a group of fatal transmissible neurodegenerative disorders of animals and humans caused by prions. Our major objectives are to use proven transgenic (Tg) approaches to study the means by which primary structure elements of the prion protein (PrP) and prion strain properties influence CWD transmission barriers to address the origins of CWD and the prevalence of CWD strains and to determine the mechanism of prion transmission among cervids. Three Specific Aims are proposed: (1) To use Tg mice expressing cervid (Cer) PrP [Tg(CerPrP)] that simulate disease in deer and elk to study the mechanisms of CWD transmission among cervids and sub-clinical CWD replication in the absence of accumulation of conventional forms of pathogenic PrP; (2) To use Tg approaches to assess the influence of CWD strain variation and CerPrP polymorphisms on CWD pathogenesis and to address the disease-causing potential of CWD strains in other species; and (3) To probe the molecular basis of species-dependent CWD transmission barriers using novel chimeric murine/CerPrP constructs and an innovative combination of Tg approaches and in vitro PrP amplification. Addressing the mechanism of CWD transmission will lead to better CWD control in cervid populations and allow more accurate assessments of the risks posed to humans and livestock from exposure to CWD. The proposed studies will also further our understanding of the general molecular events underlying prion propagation species barriers and prion strains that will ultimately result in rational therapeutic and diagnostic approaches for human and animal prion diseases and will provide important information about the molecular nature of the infectious agent in the contexts of clinical and sub-clinical prion disease.

project_terms:
Address;Affect;Animals;Biochemical;Biological;Biological Assay;Blood;Body Fluids;Brain;Cattle;Cell Line;Cells;Chronic Wasting Disease;Clinical;Deer;Development;Diagnostic;Disease;Elements;Equus caballus;Event;Excretory function;Exposure to;Genetic Polymorphism;Genotype;Hand;Hippocampus (Brain);Human;In Vitro;Infectious Agent;Investigation;Knockout Mice;Lead;Leucine;Livestock;Methionine;Modeling;Molecular;Molecular Conformation;Molecular Probes;Mus;Nature;Neuraxis;Neurodegenerative Disorders;Neurons;PAWR protein;Pathogenesis;Pathology;Peptide Hydrolases;Play;Population;Positioning Attribute;PrPSc Proteins;Predisposition;Prevalence;Prion Diseases;Prions;Production;Property;Reporting;Research;Research Personnel;Resistance;Resources;Risk;Risk Assessment;Role;Sampling;Simulate;Skeletal muscle structure;Source;Specificity;Structure;Therapeutic;Time;Titrations;Transgenic Organisms;Variant;base;cervid;design;disease transmission;disorder control;innovation;neuropathology;novel;programs;transmission process


application_id: 7871859
project_number: 3R01NS039041-10S2
project_title: Neurogeneic Amplification of Pancreatitis Pain
administering_ic: NINDS
award_notice_date: 2009-08-28
application_type: 3
activity_code: R01
ic: NS
serial_number: 039041
suffix: S2
program_official: PORTER, LINDA L
project_start_date: 2000-04-01
project_end_date: 2010-03-31
study_section: Special Emphasis Panel[ZRG1-IFCN-5(04)M]
contact_pi_person_id: 6346300
contact_pi: WESTLUND-HIGH, KARIN N.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Many patients with pancreatitis or pancreatic cancer complain of abdominal pain that is resistant even to morphine. Our previous studies have determined that pain in patients with cancer involving the pelvic visceral organs is relieved by a neurosurgical lesion limited to the midline of the dorsal column of the spinal cord. We determined that sensory input from the pancreas is primarily transmitted to higher brain sensory processing centers as a midline component of the postsynaptic dorsal column pathway using anatomical electrophysiological and behavioral methods. In our laboratory recently we have developed a model of persistent visceral pain in Lewis inbred rats that resembles human pancreatitis in blood values and histology. The purpose of the proposed project is to study the neuronal pathway by which pain signals from the pancreas reach higher brain centers and how sensitization of this pathway can lead to persistent pain states. A multidisciplinary approach is used including behavioral electrophysiological and functional magnetic resonance imaging (fMRI) methods. The following hypothesis and specific aims were devised to improve our understanding of chronic visceral pain processing toward the long term goal of improved therapy: HYPOTHESIS: Nociceptive information arising from the inflamed pancreas is relayed in the spinal cord transmitted through medially ascending pathways to higher centers and produces central sensitization in medially located brain structures. Specific Aim 1 is to determine the nociceptive pathways activated in persistent pancreatitis. Specific Aim 2 is to reduce activation in the visceral nociceptive pathways maintaining central sensitization in a persistent pancreatitis model in Lewis inbred rats. The long-term outcome expected is that information about the visceral nociceptive pathway will contribute to future identification of therapeutic targets for these devastatingly painful conditions involving the pancreas.

project_terms:
Abdominal Pain;Animals;Behavioral;Blood;Blood Volume;Brain;Cell Nucleus;Cells;Central cord canal structure;Characteristics;Chest;Chronic;Clinical;Clinical Treatment;Communities;Dorsal;Endothelin;Follow-Up Studies;Functional Magnetic Resonance Imaging;Future;Goals;Histology;Human;Inbred Lew Rats;Laboratories;Lead;Lesion;Malignant Neoplasms;Malignant neoplasm of pancreas;Medial;Medical;Methods;Modeling;Morphine;Neurons;Nociception;Operative Surgical Procedures;Organ;Outcome;Pain;Pan Genus;Pancreas;Pancreatitis;Pathway interactions;Patients;Pelvic Cancer;Pelvis;Persistent pain;Physiological;Play;Pontine structure;Process;Psyche structure;Rattus;Refractory;Reporting;Research Personnel;Resistance;Role;Route;Sensory;Sensory Process;Signal Transduction;Spinal;Spinal Cord;Structure;Sympathetic Nerve Block;Syndrome;System;Thalamic structure;Visceral;Visceral Afferents;Visceral pain;cancer pain;central sensitization;clinically relevant;dorsal column;imaging modality;improved;insight;interdisciplinary approach;midbrain central gray substance;novel;postsynaptic;programs;raphe nuclei;research study;response;therapeutic target;transmission process


application_id: 7871499
project_number: 5R01DA025591-03
project_title: GABAA Modulation as a Target for Developing Medications for Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2011-03-03
opportunity_number: PA-07-333
application_type: 5
activity_code: R01
ic: DA
serial_number: 025591
program_official: BOUGH, KRISTOPHER J
project_start_date: 2008-09-15
project_end_date: 2013-02-28
study_section: ZDA1-MXH-H(22)
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): Methamphetamine dependence is a significant public-health concern. Dopamine plays a prominent role in mediating the behavioral effects of methamphetamine. ?-Aminobutyric-acid (GABA) systems inhibit dopamine systems. Increasing GABA activity may result in greater inhibition of dopamine systems and thus attenuate the behavioral effects of methamphetamine thought to contribute to its abuse. Preclinical and human laboratory experiments have demonstrated that high-efficacy GABAA receptor modulators attenuate the behavioral effects of stimulants under a variety of behavioral arrangements. These findings suggest that GABAA receptor modulation might be a viable target for the development of medications to manage methamphetamine abuse. The overarching goal of this application is to demonstrate targeting GABAA receptor modulation is a viable strategy for the development of medications to manage methamphetamine dependence. This goal will be achieved through the conduct of two "proof-of-concept" experiments designed to accomplish two specific aims.  The first specific aim is to demonstrate that a GABAA receptor modulator attenuates the reinforcing effects of methamphetamine. To accomplish this aim we will determine the reinforcing effects of intranasal methamphetamine during maintenance on a high-efficacy GABAA receptor modulator using a progressive-ratio procedure (Exp. 1). The reinforcing effects of stimulants are central to their abuse potential. By inference then an effective pharmacotherapy for managing stimulant dependence will modify drug self-administration. The second specific aim is to demonstrate that a GABAA receptor modulator attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim we will teach volunteers to discriminate intranasal methamphetamine using a drug-discrimination procedure (Exp. 2). A range of doses of methamphetamine will then be tested during maintenance on a GABAA receptor modulator and placebo. The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e. a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse.  The proposed research will provide initial clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications for methamphetamine abuse. In addition to the clinical information the proposed research will provide basic-science and translational information. First the inclusion of drug self-administration and discrimination measures along with subjective-effect questionnaires will provide information concerning the relationship between the reinforcing discriminative and subjective effects of methamphetamine. Second because GABAA receptor modulators have been tested as pharmacotherapies for stimulant dependence in laboratory animals using similar behavioral procedures the proposed research will determine albeit indirectly the extent those findings from preclinical studies generalize to humans. Public Health Relevance: Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications to manage methamphetamine dependence.

project_terms:
Admission activity;American;Aminobutyric Acids;Attenuated;Basic Science;Behavior;Behavioral;Central Nervous System Stimulants;Clinical;Cocaine;Dependence;Development;Discrimination (Psychology);Dopamine;Dose;Drug Kinetics;Educational process of instructing;Epidemiology;Foundations;Goals;Great Lakes Region;Human;Institution;Intelligence;Kentucky;Laboratories;Laboratory Animals;Learning;Location;Maintenance;Measures;Mediating;Methamphetamine;Methamphetamine dependence;Molecular;Nerve;Neurotransmitters;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pharmacotherapy;Placebos;Play;Procedures;Psychostimulant dependence;Questionnaires;Relapse;Reporting;Research;Role;Self Administration;Serotonin;Signal Transduction;Stimulus;Synapses;System;Testing;Vesicle;design;dopamine system;drug discrimination;effective therapy;gamma-Aminobutyric Acid;methamphetamine abuse;monoamine;noradrenaline transporter;novel;pre-clinical;preclinical study;prevent;public health medicine (field);public health relevance;receptor;research study;reuptake;topiramate;volunteer


application_id: 7871384
project_number: 5R01ES017260-02
project_title: Atherogenic Mechanisms of Arsenic
administering_ic: NIEHS
award_notice_date: 2010-03-25
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 017260
program_official: NADADUR, SRIKANTH
project_start_date: 2009-06-15
project_end_date: 2014-03-31
study_section: Special Emphasis Panel[ZRG1-DIG-C(90)S]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
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 overall goal of this project is to understand the mechanisms by which exposure to arsenic accelerates or aggravates atherosclerosis. Exposure to arsenic-contaminated water is a global problem and results in the manifestation of multiple cardiovascular symptoms including hypertension stroke and myocardial infarction. Increased atherosclerosis is likely to be the major underlying cause of the increased risk of cardiovascular disease in an arsenic-exposed population. Accordingly the intent of this proposal is to understand the mechanism by which arsenic accelerates or exacerbates atherogenesis in a well-controlled animal model. On the basis of supportive preliminary evidence our central hypothesis is that arsenic promotes atherogenic changes in endothelial cells and in macrophages by inducing endoplasmic reticulum (ER) stress which in turn triggers the unfolded protein response (UPR). To test this hypothesis we will: (1) delineate the contribution of ER stress and UPR to arsenic-mediated endothelial cell and macrophage activation; (2) examine the progression of atherogenesis in arsenic-exposed mice; and (3) elucidate the role of UPR in exacerbation of atherogenesis by arsenic. To accomplish these aims we will examine whether exposure to arsenic induces ER stress and triggers UPR in endothelial cells and macrophages. We will identify which aspects of the UPR are triggered by arsenic and whether ER stress contributes to arsenic-induced activation of endothelial cells and foam cell formation. To assess how arsenic affects atherogenesis we will examine early intermediate and advanced lesions for lipid accumulation cellularity inflammation and oxidative stress in apoE-null mice exposed to arsenic. Bone marrow transplants from arsenic-exposed to non-exposed mice will be performed to delineate the specific contribution of macrophages to arsenic toxicity. To identify the in vivo role of UPR in arsenic toxicity we will examine which components of ER stress and UPR are activated in the lesions of arsenic-exposed animals and whether inhibition of the adaptive phase of UPR by deleting the ATF3 gene accelerates or treatment with chemical chaperones of protein folding inhibits lesion formation. Results of this project may lead to a better understanding of the mechanisms by which arsenic affects atherogenesis and how they could be therapeutically prevented. PUBLIC HEALTH RELEVANCE: Large sections of human population in the US as well as Asia are exposed to high levels of arsenic in drinking water. Previous epidemiological studies show that people exposed to high levels of arsenic have a higher risk of developing cardiovascular disease. Nevertheless the mechanisms by which arsenic elevates cardiovascular disease risk are not known. This project is designed to mimic human exposures to arsenic in an animal model and test whether exposure to arsenic increases the rate and/or the extent of atherosclerotic lesion formation in atherosclerosis-prone mice. The project seeks to understand the underlying molecular mechanisms by which arsenic increases atherosclerosis; which processes are affected; and which cellular and molecular mechanisms mediate the cardiovascular toxicity of arsenic. Results obtained from this project are likely to provide novel models for testing atherogenic effects of arsenic exposure in developing a better understanding of how arsenic worsens atherosclerosis and how the atherogenic effects of arsenic could be ameliorated and treated.

project_terms:
Ablation;Affect;Animal Model;Animals;Apolipoprotein E;Apoptosis;Arsenic;Arterial Fatty Streak;Arteriosclerosis;Asia;Asses;Atherosclerosis;Blood;Bone Marrow;Bone Marrow Transplantation;Calcium;Cardiovascular Diseases;Cardiovascular system;Carotid Atherosclerotic Disease;Cause of Death;Cell Adhesion Molecules;Cell Death;Cellularity;Cessation of life;Chemicals;Chronic;Collagen;Control Animal;Cytokine Activation;Disease;Endoplasmic Reticulum;Endothelial Cells;Epidemiologic Studies;Exposure to;Foam Cells;Foot Diseases;Genes;Genetic;Goals;Human;Hypertension;Infant;Inflammation;Inflammatory;Ingestion;Knockout Mice;Laboratories;Lead;Lesion;Lipids;Macrophage Activation;Matrix Metalloproteinases;Measures;Mediating;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Chaperones;Mothers;Mus;Myocardial Infarction;Myocardial Ischemia;Oxidative Stress;Pathway interactions;Peripheral arterial disease;Phase;Population;Process;Production;Proteins;Risk Factors;Role;Signal Transduction;Smooth Muscle Myocytes;Staging;Stress;Symptoms;T-Lymphocyte;Testing;Toxic effect;Vascular Endothelial Cell;Water;activating transcription factor;activating transcription factor 3;arterial lesion;atherogenesis;base;biological adaptation to stress;cardiovascular disorder risk;chemokine;cytokine;design;drinking water;endoplasmic reticulum stress;exposed human population;high risk;in vivo;macrophage;novel;prevent;protein folding;public health relevance;response;stroke;transcription factor

public_health_relevance:
Large sections of human population in the US as well as Asia are exposed to high levels of arsenic in drinkingwater. Previous epidemiological studies show that people exposed to high levels of arsenic have a higher riskof developing cardiovascular disease. Nevertheless the mechanisms by which arsenic elevatescardiovascular disease risk are not known. This project is designed to mimic human exposures to arsenic inan animal model and test whether exposure to arsenic increases the rate and/or the extent of atheroscleroticlesion formation in atherosclerosis-prone mice. The project seeks to understand the underlying molecularmechanisms by which arsenic increases atherosclerosis; which processes are affected; and which cellular andmolecular mechanisms mediate the cardiovascular toxicity of arsenic. Results obtained from this project arelikely to provide novel models for testing atherogenic effects of arsenic exposure in developing a betterunderstanding of how arsenic worsens atherosclerosis and how the atherogenic effects of arsenic could beameliorated and treated.


application_id: 7870318
project_number: 5P20RR021954-03
project_title: Center of Research in Obesity and Cardiovascular Disease (1P20 RR021954-01A1)
administering_ic: NCRR
award_notice_date: 2010-06-23
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
program_official: LIU, YANPING
project_start_date: 2008-09-08
project_end_date: 2013-06-30
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
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
budget_start_date: 2010-07-01
project_abstract:
Description (provided by applicant): The objective of this revised application is to create a Center of Biomedical Research Excellence in Obesity and Cardiovascular Disease (COCVD) to identify mechanisms linking the epidemic of obesity to the high incidence of cardiovascular diseases in the obese population and to use this focus as a platform to develop promising junior project investigators and enhance their success at competing for NIH grant support. We will achieve this objective by (1) assembling a group of established extramurally-supported scientists who will mentor faculty serving as principal project investigators on research projects that address timely and significant questions related to obesity and cardiovascular disease (2) providing a variety of mentoring approaches that will facilitate the development of research projects by project investigators leading to independent NIH-supported research (3) developing and supporting shared use core facilities that support and extend research methods critical to the study of obesity and cardiovascular disease (4) providing pilot grants for new projects focused on obesity and cardiovascular diseases (5) facilitating symposia seminars and meetings of participants researching obesity and cardiovascular diseases (6) focusing on the research of the center at retreats dedicated to evaluating progress by project investigators studying obesity and cardiovascular diseases (7) strategically hiring promising new faculty to develop a critical mass of productive physician and basic scientists studying obesity and cardiovascular diseases. Five project investigators representing both physician and basic scientists will serve as principal project investigators on research projects that address a central hypothesis and that utilize a common model of diet-induced obesity to study obesity-induced hypertension atherosclerosis and platelet dysfunction/vascular inflammation. The central hypothesis of this revised proposal is that obesity induces changes in the production and release of adipokinins and other inflammatory mediators to promote cardiovascular diseases. Each project addresses aspects of this hypothesis using a common model of diet-induced obesity and the projects synergize through their focus on adipokinesis inflammation and through coordinate development of multiple cardiovascular diseases. The proposed structure and mentoring mechanisms will meet the need of increasing NIH supported research and will develop a multi-disciplinary Center around the clinically significant area of obesity and cardiovascular disease.

project_terms:
Address;Adolescent;Adult;Advisory Committees;Affect;Age;Area;Arts;Atherosclerosis;Attention;Behavioral Risk Factor Surveillance System;Blood Platelets;Blood Pressure;Cardiovascular Diseases;Cardiovascular system;Categories;Cause of Death;Centers of Research Excellence;Central obesity;Child;Cholesterol;Clinical;Core Facility;Development;Diabetes Mellitus;Diagnosis;Diet;Disease;Disease Clusterings;Dyslipidemias;Educational aspects;Environment;Epidemic;Evaluation;Exhibits;Faculty;Figs - dietary;Functional disorder;Funding;Glucose Intolerance;Goals;Grant;Guidelines;Health;Health Care Costs;High Density Lipoproteins;High Prevalence;Hyperglycemia;Hypertension;Incidence;Individual;Inflammation;Inflammation Mediators;Insulin Resistance;Journals;Kentucky;Knowledge;Link;Medical;Mentors;Metabolic syndrome;Methods;Modeling;Mus;N.I.H. Research Support;NHANES;National Center for Research Resources;National Heart Lung and Blood Institute;National Institute of Diabetes and Digestive and Kidney Diseases;Obesity;Obesity associated disease;Outcome;Overweight;Participant;Patients;Phenotype;Physicians;Pilot Projects;Population;Prevalence;Production;Program Research Project Grants;Publications;Research;Research Infrastructure;Research Methodology;Research Personnel;Research Project Grants;Resources;Risk;Risk Factors;Scientist;Source;Strategic Planning;Structure;Syndrome;Thrombosis;Time;Training Support;Translating;Triglycerides;United States National Institutes of Health;Universities;adipokines;clinically significant;improved;interest;meetings;member;news;prevent;programs;skills;statistics;success;symposium;vascular inflammation


application_id: 7870302
project_number: 5R01AG024040-05
project_title: Genetic and Environmental Risk Factors for PSP
administering_ic: NIA
award_notice_date: 2010-07-19
opportunity_number: PAS-03-092
application_type: 5
activity_code: R01
ic: AG
serial_number: 024040
program_official: MILLER, MARILYN
project_start_date: 2006-07-15
project_end_date: 2013-06-30
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 2452926
contact_pi: LITVAN, IRENE
other_pis: Not Applicable
congressional_district: 03
department: NEUROLOGY
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): Progressive supranuclear palsy (PSP) is a sporadic tauopathy with unknown cause. The H1 tau haplotype is implicated in its etiology; however it is also present in 60% of normal controls. This coupled with late symptom onset indicates that genetics alone does not cause PSP. Support for the environmental factor hypothesis stems from animal models and the observed association between PSP and exposure to mitochondrial complex I inhibitors (i.e. acetogenins) which are neurotoxic to dopaminergic neurons. Impaired metabolism in PSP mitochondria and oxidative injury in affected brain areas also support this hypothesis. Hence genes and environment may both play a role either alone or through their interactions. This application will determine: 1) if there is an association between PSP and the HI/HI genotype specific HI sub-haplotypes alpha-synuclein polymorphisms or parkin gene deficits or if there are gene-gene interactions; 2) if there is an association between PSP occupational and/or environmental chemical exposures functionally or structurally similar to rotenone/acetogenins; and 3) if hypertension or traumatic brain injury prior to symptom-onset is associated with PSP. To disentangle the complex etiology of PSP this case-control multicenter study involves 500 PSP cases 500 age/gender matched primary controls and 500 secondary controls for genetic confirmation. Previous case-control studies have been inconclusive because of limitations in size scope or structure. This is the first adequately powered series of PSP cases with matched controls that has the necessary infrastructure to address our hypotheses and explore gene-environmental interactions. As a result it will help resolve controversies concerning the cause(s) of PSP and will stimulate new avenues of pathogenesis research and prophylactic therapies. Understanding the etiology of PSP may also help explain the causes of other tauopathies such as Alzheimer's disease. This multidisciplinary team of movement disorder specialists epidemiologists geneticists biostatisticians industrial hygienist and toxicologist is well suited to unravel the complex etiology of PSP. The use of the NINDS cell repository for genetic banking will also allow DNA sample sharing with other investigators.

project_terms:
Address;Affect;Age;Alzheimer's Disease;Animal Model;Area;Brain;Carbon Disulfide;Carbon Monoxide;Case-Control Studies;Cells;Chemicals;Chronic;Clinical;Collaborations;Complex;Coupled;DNA;Deltastab;Development;Diagnosis;Disease;Enrollment;Environment;Environmental Exposure;Environmental Risk Factor;Epidemiologist;Etiology;Exposure to;Family;First Degree Relative;Future;Gender;Gene Mutation;Genes;Genetic;Genetic Polymorphism;Genotype;Goals;Haplotypes;Herbicides;Hypertension;Injury;Intervention;Knowledge;Lead;Manganese;Metabolism;Methodology;Mitochondria;Movement Disorders;Multicenter Studies;Mutation;National Institute of Neurological Disorders and Stroke;Neurodegenerative Disorders;Occupational;Organic solvent product;Other Genetics;Parkin gene;Pathogenesis;Patients;Pattern;Pesticides;Play;Progressive Supranuclear Palsy;Promotor (Genetics);Questionnaires;Recording of previous events;Research;Research Infrastructure;Research Personnel;Resources;Risk;Risk Factors;Role;Rotenone;Sampling;Secondary Parkinson Disease;Series;Severity of illness;Site;Specialist;Structure;Suggestion;Symptoms;Tauopathies;Testing;Tetrahydroisoquinolines;Transition Elements;Traumatic Brain Injury;Variant;Variation (Genetics);Work;acetogenin;alpha synuclein;base;carbamate insecticide;case control;design;dopaminergic neuron;environmental chemical exposure;gene interaction;genetic risk factor;high risk;inhibitor/antagonist;leucine-rich repeat kinase 2;multidisciplinary;neurotoxic;parkin gene/protein;programs;prophylactic;repository;sodium arsenite;stem;tau Proteins;tau-1


application_id: 7869821
project_number: 3R01AR055246-02S2
project_title: Circadian rhythms and skeletal muscle
administering_ic: NIAMS
award_notice_date: 2009-06-15
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: AR
serial_number: 055246
suffix: S2
program_official: BOYCE, AMANDA T
project_start_date: 2008-03-01
project_end_date: 2013-02-28
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary:Circadian rhythms have long been known to influence behavioral and biological processes such as physicalactivity and feeding behavior. The fundamental importance of this system which works to link physiology withthe day/night cycle is underscored by its presence in every known species and the growing evidence linkingalterations in core clock function and diseases such as cancer diabetes and mental health.Recent studies from our laboratory have shown that mutations of the canonical circadian genes Clock andBmal1 dramatically disrupt muscle function. This is the first genetic evidence linking skeletal muscle functionto circadian rhythms. Expression profiling studies of skeletal muscle over 48 hours identified that MyoD is acircadian gene. Molecular experiments went on to demonstrate that the MyoD promoter is directly bound andregulated by the core clock factors CLOCK and BMAL1.The studies outlined in this proposal combine molecular cell biological and biophysical approaches tounderstand the mechanisms by which the core clock mechanism is regulated in skeletal muscle and how lossof this rhythm leads to altered MyoD expression and loss of muscle function. The hypotheses for thisproposal are 1) Synchronization of core clock gene expression in skeletal muscle requires intact innervation2) Muscle specific mutations of Bmal1 or Clock will be sufficient to cause arrhythmic MyoD expression andmuscle dysfunction 3) Loss of maximal force capacity/specific tension in muscle of circadian clock-compromised mice is due to decreased actin:myosin interaction resulting from disruption of sarcomericstructure and/or altered stoichiometry of myofilament proteins.The results of the experiments outlined in this proposal have significant implications for maintenance ofmuscle with an impact on our understanding and treatment of sarcopenia muscle wasting/cachexia andproblems associated with metabolic diseases such as insulin resistance. In addition our understanding ofcircadian regulation of skeletal muscle will have likely applications for rehabilitation therapies for spinal cordinjury patients and people that are exposed to prolonged periods of bedrest. Project NarrativeThe results of the proposed work will determine the role of the biological clock in maintainingnormal skeletal muscle structure and function. The findings have significant implications formaintenance of muscle with an impact on our understanding and treatment of sarcopeniamuscle wasting/cachexia and problems associated with metabolic diseases such as insulinresistance. In addition our understanding of circadian regulation of skeletal muscle will havelikely applications for rehabilitation therapies for spinal cord injury patients and people that areexposed to prolonged periods of bedrest.

project_terms:
Actinin;Actins;Aging;Bed rest;Behavior;Binding (Molecular Function);Biological;Biological Clocks;Biological Process;Brain;Cachexia;Cell physiology;Cells;Chronic Disease;Circadian Rhythms;Clinical;Complement;Development;Diabetes Mellitus;Disease;Down-Regulation;Electron Microscopy;Enhancers;Feedback;Feeding behaviors;Fiber;Fluorescence Microscopy;Functional disorder;Gel;Gene Expression;Gene Proteins;Gene Targeting;Genes;Genetic;Genetic Transcription;Hour;Hypothalamic structure;In Situ Hybridization;Insulin Resistance;Intrinsic drive;Knock-out;Laboratories;Lesion;Link;Liver;Maintenance;Malignant Neoplasms;Mammals;Measures;Mechanics;Mental Health;Metabolic Diseases;Microfilaments;Molecular;Molecular Profiling;Mus;Muscle;Muscle Fibers;Muscle function;Mutant Strains Mice;Mutation;Myosin ATPase;Myosin Heavy Chains;Normal Cell;Operative Surgical Procedures;Pattern;Peripheral;Physical activity;Physiology;Promotor (Genetics);Protein Isoforms;Proteins;Regulation;Rehabilitation therapy;Role;Skeletal muscle structure;Spinal cord injury patients;Structure;System;Time;Tissues;Translations;Work;behavior influence;circadian pacemaker;connectin;cryptochrome;design;mutant;nebulin;nerve supply;novel;rehabilitation strategy;research study;sarcopenia;skeletal;stoichiometry;suprachiasmatic nucleus;transcription factor;wasting


application_id: 7869581
project_number: 3P01NS058484-03S2
project_title: Calpain as a Therapeutic Target for TBI (P01)
administering_ic: NINDS
award_notice_date: 2009-08-17
application_type: 3
activity_code: P01
ic: NS
serial_number: 058484
suffix: S2
program_official: HICKS, RAMONA R
project_start_date: 2007-05-01
project_end_date: 2011-08-31
study_section: ZNS1-SRB-R(24)
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
The overall goal of this PPG is to evaluate the hypothesis that calpain inhibition represents a viable
therapeutic target for intervention following traumatic brain injury (TBI). TBI represents a leading cause of
death and disability in adults and children and improved treatment options are urgently needed. Calpains
are excessively activated following TBI and are strongly implicated in the secondary neuronal degeneration.
The resultant hypothesis is that calpain inhibition will protect against the pathological and functional
consequences of TBI. Although straightforward this hypothesis has proven to be surprisingly difficult to
evaluate. A handful of studies in animal models of TBI have demonstrated improved neurological recovery
and attenuated axonal injury with calpain inhibitor treatment. However evidence that these benefits are
directly related to calpain inhibition has been elusive. Moreover there are numerous unanswered questions
regarding the mechanisms by which calpains contribute to cell death and dysfunction. This PPG brings
together investigators with strong expertise in calpain biochemistry and in animal models of TBI to evaluate
three distinct mechanisms of calpain inhibition following TBI. Project 1 explores the role of the endogenous
specific and potent calpain inhibitor calpastatin in modulating calpain function and improving outcome
following TBI. Project 2 is translational and will investigate the ability of new small molecule calpain inhibitors
to attenuate the pathological and functional consequences of TBI. Project 3 will examine the roles of
individual calpain isoforms in neurodegeneration and TBI focusing on the hypothesis that u-calpain is a
pathologic isoform and is localized to mitochondria. In addition to the three projects there will be three cores:
A Administrative and Biostatistical Core; B Animal Core; and C Proteomics and Biomarker Core. Together
these projects and cores will provide a clear indication as to whether calpain inhibition represents a viable
therapeutic target for TBI and whether the small molecule calpain inhibitors are suitable for subsequent
preclinical and clinical investigation.


application_id: 7869432
project_number: 5P50DA005312-19
project_title: IMPROVING EFFECTIVE DESIGN AND TARGETING OF SUBSTANCE AUBSE PREVENT MESSAGES
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1
subproject_number: 0014
contact_pi_person_id: 1963601
contact_pi: ZIMMERMAN, RICK S.
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: 2009-07-01
budget_end_date: 2010-06-30
funding_mechanism: Research Centers
project_abstract:
Interventions to prevent or reduce substance use or abuse among young adults are few and generallynot effective. This is unfortunate as young adults are among the most frequent users of a varietyofsubstances including marijuana alcohol and various illicit substances. Most substance abuse preventiveinterventions have largely ignored biologically-basedpredispositions that lead individuals both to engage inrisky behaviors including substance use and to attend and respond to certain kinds of interventionmessages. This project builds on our previous work using sensation seeking to target and tailor messagesaimed at reducing substance use and risky sexual behavior Specifically building on emerging research fromthe Center wedecompose sensation seeking into its component parts of reward-seeking and inhibition.Drawing on recent advances in message targeting and tailoring we move beyond our previous work onmessage sensation value to include consideration of the influence of message framing and fear on messageeffectiveness. The present proposal offers and tests a general model of message effectivenessthatconsiders the interaction between individual differences (i.e. reward seeking and inhibition) and messagecharacteristics (i.e. message sensation value framing and fear). The model is tested in three studies usingpublic service announcements (PSA) an intervention mode with which our team has extensive experience. There are four specific aims: 1) To examine the persuasive effects of high vs. low sensation value (HSVvs. LSV) substance abuse prevention messages on young adults varying in reward seeking and inhibition;2) To examine the persuasive effects of two emotion-based dimensions of substance abuse messages:message framing (gain vs. loss-framed [GF vs. LF]) and fear (high vs. low threat [HT vs. LT]) on youngadults varying in their levels of reward seeking and inhibition.; 3) To assess the extent to which thedifferential persuasive effects of HSV vs. LSV GF vs. LF and LT vs. HT substance abuse preventionmessages generalize to another high-risk behavior risky sex; and 4) Develop and pilot-test the effectivenessof substance abuse prevention public service announcements (PSAs) with young adults who are either highin reward seeking low in inhibition or both. We propose to accomplish these aims through three studies.The first examines the impact of message sensation value framing and fear on message effectiveness forPSAs aimed at reducing marijuana use as a function of reward seeking and inhibition; the second tests theboundaries of our model using PSAs aimed at reducing risky sexual behavior; the third begins the process ofdesigning optimally effective PSAs based on previous results. Outcomes from the experiments andqualitative studies proposed in this project may be immediately applied to an established body of workboth ours and others in the development of PSAs that are targeted at the reduction of marijuana use.

project_terms:
Accounting;Address;Affective;Alcohol or Other Drugs use;Alcohols;Anxiety;Attention;Attitude;Behavior;Characteristics;Complex;Data;Development;Dimensions;Drug abuse;Effectiveness;Elements;Emotions;Esthesia;Failure (biologic function);Fright;Impulsivity;Individual;Individual Differences;Intervention;Knowledge;Lead;Literature;Marihuana;Marijuana Smoking;Modeling;Outcome;Personality;Predisposition;Prevention;Prevention program;Preventive Intervention;Probability;Process;Reaction;Reading;Recording of previous events;Research;Research Personnel;Review Literature;Rewards;Risk;Risk Behaviors;Risk-Taking;Schools;Services;Simplexvirus;Specific qualifier value;Substance abuse problem;Teenagers;Testing;Translational Research;Work;base;design;experience;high risk behavior;high risk sexual behavior;improved;member;novel;prevent;programs;research study;sex;substance abuse prevention;success;trait;willingness;young adult


application_id: 7869431
project_number: 5P50DA005312-19
project_title: MEDIATING PROCESSES IN THE PERSONALITY SUBSTANCE USE RELATION
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1
subproject_number: 0013
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: 2009-07-01
budget_end_date: 2010-06-30
funding_mechanism: Research Centers
project_abstract:
To optimally design targeted interventions aimed at reducing substance use one must know whichcharacteristics or traits are involved in substance use and how these characteristics lead to substanceuse;these relations are likely to be complex and to involve bi-directional influences. The present project focuseson two separable traits related to substance use: reward seeking defined as a tendency to enjoy and pursueexciting activities and new experiences and low inhibition defined as the tendency to act without thinking orreflection. The research primarily examines basic elemental processes (e.g. risk tolerance inhibitorycontrol delay discounting Behavioral Inhibition or Activation System functioning) that may mediate therelations between these traits and substance use. The elemental processes are hypothesized to reflect theactivity of two biological systems: an approach/reward seeking system and an inhibitory system. The rewardsystem is theorized to be responsive to reward and is responsible for activating approach behavior. Theinhibition system is theorized to be sensitive to punishment and is responsible for inhibiting ongoing behaviorand initiating active information processing. Several potential social variables are also examined as potentialmediators (i.e. substance use expectancies and peers). The research also allows for the possibility thatsubstance use itself changes the traits and the underlying elemental processes. Finally the project examinesthe interrelations among the elemental processes themselves. All of these issues are examined in thecontext of a three-year two cohort longitudinal study. There are four specific aims:1. To identify the mechanisms underlying the relations leading from reward seeking and inhibition tosubstance use. Inhibition and reward seeking are distinct traits with distinct outcomes including substanceuse and abuse. Little is known however about the processes that link these traits to their outcomes.2. To examine the effect of substance use on the processes associated with reward seeking and inhibition.Research has shown acute effects of drug exposure on the processes under study. For examplealcoholhas been shown to have acute effects on inhibitory control. Additionally a number of studies havedemonstrated process deficits in substance abusers. Thus it is possible that drug use influences theprocesses underlying reward seeking and inhibition although this has not been demonstrated longitudinally.3. To examine the relations among the underlying processes themselves. The processes examined in thepresent research come from a variety of levels and modes of assessment ranging from elementary inhibitorycontrol through Behavioral Inhibition System functioning assessed via psychophysiology. Although each taskand measure is related to substance use and has been designed to assess one of the two hypotheticalsystems these tasks have not been examined together previously.

project_terms:
Acute;Alcohol consumption;Alcohol or Other Drugs use;Alcohols;Behavior;Behavioral inhibition;Cardiac;Characteristics;Complex;Cues;Drug Exposure;Drug abuse;Drug usage;Elements;Esthesia;Expectancy;Failure (biologic function);Galvanic Skin Response;Incentives;Intervention;Lead;Left;Link;Longitudinal Studies;Measures;Mediating;Mediator of activation protein;Motivation;Names;Outcome;Personality;Pharmaceutical Preparations;Process;Psychophysiology;Punishment;Reaction Time;Research;Research Personnel;Rewards;Risk;Risk Factors;Short-Term Memory;Signal Transduction;System;Thinking function;Time;Translational Research;Withdrawal;analog;approach behavior;biological systems;cognitive system;cohort;design;discount;discounting;experience;information processing;longitudinal design;peer;programs;response;social;substance abuser;trait


application_id: 7869410
project_number: 5R01DK074816-04
project_title: Albumin-AFP Gene Family Regulation in Fetal and Adult Liver
administering_ic: NIDDK
award_notice_date: 2010-06-25
application_type: 5
activity_code: R01
ic: DK
serial_number: 074816
program_official: SERRANO, JOSE
project_start_date: 2007-09-01
project_end_date: 2012-06-30
study_section: Gastrointestinal Cell and Molecular Biology Study Section[GCMB]
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
budget_start_date: 2010-07-01
project_abstract:
DESCRIPTION (provided by applicant): Mammalian liver development requires the sequential activation of genes in a highly ordered manner. Once activated levels of gene expression in the liver must continually be responsive to extracellular signals in order for organisms to maintain physiological homeostasis. We have been studying the mouse alpha- fetoprotein (AFP) gene as a model of liver-specific gene regulation. These studies have focused on the AFP enhancer region. More recently we have become increasingly interested regulation of all genes in the albumin-AFP gene family. One main goal of this proposal is to investigate the role of the AFP enhancers in the control of this gene family in the liver. Since AFP is activated in the fetal liver shut-off at birth and reactivated in models of liver damage and liver cancer these studies should help elucidate the basis of transcriptional changes that occur during liver damage and hepatocarcinogenesis. We are also interested in studying the process of zonal regulation in the adult liver. Zonal gene expression is a mechanism that allows different subpopulations of hepatocyte in the liver to carry out distinct metabolic activities. The zonal gene regulation can be disrupted in damaged liver and in neoplastic liver cells. Since zonal gene regulation is essential for the liver to carry out its normal function it is important to understand the basis for this control in the normal and diseased liver.

project_terms:
Adult;Albumins;Binding (Molecular Function);Binding Proteins;Birth;Chromosomes;Complement 3c;Development;Elements;Enhancers;Family;Fetal Liver;Gene Activation;Gene Expression;Gene Expression Regulation;Gene Family;Genes;Glutamate-Ammonia Ligase;Goals;Hepatocarcinogenesis;Hepatocyte;Homeostasis;Human;Indium;Link;Liver;Malignant neoplasm of liver;Mammals;Mediating;Metabolic;Methods;Modeling;Molecular;Molecular Conformation;Mus;Neoplastic liver;Nucleic Acid Regulatory Sequences;Organism;Positioning Attribute;Process;Promoter Regions (Genetics);Promotor (Genetics);Rattus;Regulation;Regulatory Element;Repression;Role;Signal Transduction;Testing;Time;Transgenic Organisms;Vitamin D-Binding Protein;alpha-Fetoproteins;base;comparative genomics;extracellular;fetal;interest;member;postnatal;research study


application_id: 7868609
project_number: 3U10HD045934-05S1
project_title: Center for Pediatric Clinical Pharmacology Research
administering_ic: NICHD
award_notice_date: 2009-07-16
opportunity_number: RFA-HD-03-001
application_type: 3
activity_code: U10
ic: HD
serial_number: 045934
suffix: S1
program_official: GIACOIA, GEORGE
project_start_date: 2004-03-08
project_end_date: 2010-12-31
study_section: ZHD1-DSR-A(01)
contact_pi_person_id: 2311234
contact_pi: SULLIVAN, JANICE E
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
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):  This proposal is submitted in response to RFA HD-O3-O01 to obtain support for the KCPCRU Louisville KY as a sites in the NICHD PPRU Network. Long-term proqrammatic objectives of this proposal are: 1) To expand the active participation of the KCPCRU in multi-centered collaborative Clinical trials for the purpose of generating high-quality scientIfic and clinical data to support age-appropriate labeling of new currently marketed and off-patent pharmacologic agents in newborns infants and children 2) To further develop the interactive network of basic and clinical scientists at the University of Louisville dedicated to conducting translational research with a focus on characterizing the effect of human development on biologic targets key pathogenic mediators and physiologic surrogates of pharmacologic response in children 3) To fulfill the educational mission through the development of a multi-disciplinary training program in which physicians pharmacists and nurses can gain expertise in Pediatric Clinical Pharmacology. These objectives will be accomplished by the following specific aims: 1) To design and conduct collaborative clinical trials within the PPRU network NICI-ID NIH and FDA regarding pharmacokinetics pharmacodynamics safety and efficacy of new currently marketed and off-patent pharmacologic agents in preterm and term newborns infants children and adolescents Priority will be given to PPRU network studies 2) To develop an independent "mini-core" of the U of L Proteomics Laboratory that will serve as a complementary resource for network-sponsored trials and support the application of novel proteomic techniques in pediatric pharmacology studies 3) To apply proteomic techniques to identify develop validate andlor extrapolate from adult studies on biomarkers of diagnosis prognosis efficacy toxicity and disease activity 4) To characterize the effects of development disease and genetics on biologic targets key pathogenic mediators and physiologic surrogates of pharmacologic response in children using a translational science approach 5) To promote the development of students residents fellows and junior faculty in the discipline of Pediatric Clinical Pharmacology by providing a multi-faceted training experience encompassing clinical service research and didactic lectureship. The investigators and applicant institution are caoable of achieving these aims based upon: 1 )an excellent infrastructure to support the clinical and laboratory research components of our program 2)collective expertise in clinical and basic science aspects of pediatric clinical pharmacology research 3)previous and current research accomplishments including those resulting from collaborative investigations with existing PPRU network sites 4) the presence of a multi-disciplinary collaborative network of basic and clinical research scientists dedicated to the conduct of clinical pharmacology studies in children 5)presentation of 4 novel research proposals that speak directly to the program objectives and that are ideally suited for conduct within the PPRU network.

project_terms:
Address;Adolescent;Adult;Age;Basic Science;Child;Childhood;Clinical;Clinical Data;Clinical Pharmacology;Clinical Research;Clinical Services;Clinical Trials;Development;Diagnosis;Discipline;Disease;Drug Kinetics;Faculty;Health Services Research;Hereditary Disease;Human Development;Institution;Investigation;Label;Laboratories;Laboratory Research;Legal patent;Marketing;Mediator of activation protein;Metabolism;Mission;National Institute of Child Health and Human Development;Newborn Infant;Nurses;Pharmacists;Pharmacodynamics;Pharmacology;Physicians;Physiological;Proteomics;Research;Research Infrastructure;Research Personnel;Research Proposals;Resources;Safety;Scientist;Site;Students;Techniques;Toxic effect;Training;Training Programs;Translational Research;United States National Institutes of Health;Universities;absorption;base;biomarker;design;experience;novel;outcome forecast;pediatric pharmacology;programs;response


application_id: 7868062
project_number: 5R01HL083320-05
project_title: Metabolic Mechanisms of Cardiac Injury and Protection
administering_ic: NHLBI
award_notice_date: 2010-06-25
application_type: 5
activity_code: R01
ic: HL
serial_number: 083320
program_official: WONG, RENEE P
project_start_date: 2006-07-15
project_end_date: 2013-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
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: 2010-07-01
project_abstract:
DESCRIPTION (provided by applicant): Identification of fundamentally cytoprotective pathways in the myocardium lingers as an elusive challenge. Although ischemic preconditioning may be the most powerful experimental cardioprotective strategy known little clinical application has resulted from its discovery. Based on the premise that transient metabolic alterations occur during ischemic preconditioning the PI has developed a novel hypothesis wherein activation of a metabolic signal exerts protective effects. Emerging evidence indicates that global increases in levels of a specific serine/threonine post-translational modification beta-O-linked N-acetylglucosamine (O-GlcNAc) protects cell lines against injury. Here the PI will attempt to establish this modification as a novel cardiac survival signal and elucidate its potential involvement in myocardial ischemia-reperfusion injury. The general structure of this proposal is designed to answer the questions: What happens to O-GlcNAc levels during ischemia-reperfusion and preconditioning? Is the O-GlcNAc signal sufficient for cardioprotection? What are the target(s) in this process? Does this potentially protective pathway result in chronic improvement in cardiac function? In Specific Aim I (SA I) the applicant will identify temporal changes in O-GlcNAc levels during myocardial ischemia-reperfusion and following ischemic preconditioning. Using complementary pharmacology adenoviral gene transfer and RNA interference-mediated translational silencing the PI will evaluate whether augmentation of O-GlcNAc levels attenuates cardiac injury following in vivo ischemia or in vitro hypoxia-reoxygenation (SA II). Next the applicant will characterize the downstream targets namely in the mitochondria (e.g. KATP) of O-GlcNAc-mediated protection using isolated myocytes exposed to hypoxia-reoxygenation and in vivo myocardial ischemia-reperfusion (SA III). Lastly the PI will ascertain whether acute O-GlcNAc-mediated protection improves long-term cardiac function in vivo following myocardial infarction (SA IV). Data garnered from such innovative studies may establish a novel paradigm in the mechanism of post-ischemic cardiac injury and protection. Possible findings during this project will allow the development of new strategies to combat acute myocardial infarction in patients. LAY SUMMARY: The applicant will focus on a poorly understood metabolic pathway to evaluate the mechanisms of injury during a heart attack. Information gathered from this proposal may help treat heart disease.

project_terms:
Acetylglucosamine;Acute;Acute myocardial infarction;Address;Affect;Attenuated;Biological Preservation;Cardiac;Cardiac Myocytes;Cell Line;Cessation of life;Chronic;Cytoprotection;Data;Development;Enzymes;Fostering;Functional disorder;Gene Transfer;Genetic;Goals;Heart Diseases;Heat-Shock Proteins 70;Hypoxia;In Vitro;Injury;Ischemia;Ischemic Preconditioning;Knowledge;Link;Mediating;Mediator of activation protein;Metabolic;Metabolic Pathway;Mitochondria;Modality;Modification;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardial Ischemic Preconditioning;Myocardium;Pathway interactions;Patients;Pharmacology;Post-Translational Protein Processing;Process;Pump;RNA Interference;Reperfusion Injury;Reperfusion Therapy;Role;Serine;Severities;Signal Transduction;Structure;Threonine;Tissues;Transfer RNA;base;clinical application;combat;design;glucose metabolism;improved;in vivo;information gathering;innovation;novel;preconditioning;protective effect


application_id: 7867974
project_number: 5K01CA133138-03
project_title: Promoting Mammography in African American Women Visiting the Emergency Department
administering_ic: NCI
award_notice_date: 2010-05-19
opportunity_number: PAR-06-220
application_type: 5
activity_code: K01
ic: CA
serial_number: 133138
program_official: OJEIFO, JOHN O
project_start_date: 2008-06-12
project_end_date: 2013-05-31
study_section: Education Study Section (G)[NCI-G]
contact_pi_person_id: 8003903
contact_pi: HATCHER, JENNIFER
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Breast cancer is a pressing public health concern. It is the most common cancer and the second leading cause of cancer death among African American women. Screening mammography is the single most effective method of early detection of breast cancer; however African American women are screened at suboptimal rates with only 53% of African American women aged 40 and older having had a mammogram within the past year. Low income women women without health insurance and those without a usual source of health care have even lower screening rates of 44% 34% and 28% respectively. Many of these women use the Emergency Department as the only source of medical care. Through a training plan of mentoring by a team of interdisciplinary cancer control and nursing scientists formal class work and seminars this K01 Award will provide the applicant with the opportunity to develop and conduct a study that pilot tests a culturally tailored stage matched intervention delivered by peer educators to increase mammography use among African American women visiting the Emergency Department. The specific aims of the study are: (1) to examine the barriers and benefits that influence the use of screening mammography among African American women and develop a peer educator delivered intervention and tailored educational materials; (2) to develop and evaluate culturally tailored stage appropriate mammography educational materials for African American women to determine cultural acceptability readability and applicability for women visiting the Emergency Department; and (3) to compare in a randomized controlled trial with a sample of African American women the effect of two different interventions (a culturally tailored stage-matched peer educator breast cancer intervention versus tailored educational materials only) on receipt of a screening mammogram and knowledge of and intent to follow screening guidelines. The proposed study's conceptual framework integrates concepts from both the Health Belief Model and the Transtheoretical Model. These specific aims correspond to three phases: a qualitative phase a developmental phase and an intervention phase. The combination of this progressive research project and the structured training plan will prepare the applicant to meet the long-term goal of becoming an independent investigator by allowing her to develop skills in mixed methodology refine skills in advanced quantitative research methods incorporate communication in cancer control theory and principles and demonstrate the ability to integrate knowledge and experience related to health disparities and cancer control into the design and implementation of a randomized controlled clinical trial. In addition the results from the proposed project will form the foundation for further research to promote the use of screening mammography among this vulnerable group of women.

project_terms:
Accident and Emergency department;Address;African;African American;American;Breast Cancer Early Detection;Cancer Control;Cancer Etiology;Cancer Intervention;Caring;Cessation of life;Communication;Development;Discipline of Nursing;Educational Materials;Evaluation;Foundations;Goals;Guidelines;Health Insurance;Healthcare;Intervention;Knowledge;Low income;Mammography;Medical;Mentored Research Scientist Development Award;Mentors;Methodology;Methods;Modeling;Movement;Phase;Pilot Projects;Qualitative Research;Randomized Controlled Clinical Trials;Randomized Controlled Trials;Readability;Research;Research Methodology;Research Personnel;Research Project Grants;Sampling;Schedule;Scientist;Screening procedure;Second Primary Cancers;Services;Source;Staging;Structure;Testing;Training;Visit;Vulnerable Populations;Woman;Work;aged;cancer prevention;design;experience;health belief;health disparity;malignant breast neoplasm;meetings;peer;public health medicine (field);research study;skills;theories


application_id: 7867831
project_number: 5R01HL059378-12
project_title: Cardiac Metabolism of Enals
administering_ic: NHLBI
award_notice_date: 2010-06-07
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 059378
program_official: LIANG, ISABELLA Y
project_start_date: 1998-12-01
project_end_date: 2012-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
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 overall aim of this proposal is to understand the mechanisms by which oxidative stress contributes to ischemic injury in the heart. Our working hypothesis is that reactive oxygen species (ROS) generated during ischemia-reperfusion initiate lipid peroxidation reactions and that unsaturated aldehydes (enals) generated from oxidized lipids trigger and sustain myocardial oxidative stress during ischemia-reperfusion. To asses the contribution of lipid oxidation derived enals we have in the past studied the biochemical pathways of enal metabolism. Our studies show that in the heart enals are metabolized by aldose reductase (AR) aldehyde reductase and glutathione-S-transferases. Metabolism via AR appears critical because the enzyme is activated during ischemia and inhibition of the enzyme abolishes the cardioprotective effects of ischemic preconditioning. Using AR to interrogate the role of enals in ischemia-reperfusion injury we now plan to test the hypothesis that accumulation of enals and their protein adducts in the ischemic heart triggers stress responses and cell death. We propose that these responses are mediated in part by endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) and that AR metabolism decreases myocardial injury by diminishing ER stress. The specific aims of the project are to: (1) delineate the contribution of UPR to enal- induced myocardial injury; (2) elucidate the role of AR in regulating enal-induced ER stress; and (3) to examine the role of AR in preventing ER stress and UPR in hearts subjected to coronary ligation and reperfusion in situ. To accomplish these aims we will examine specific components of the UPR triggered in isolated murine hearts and myocytes determine how pharmacological inhibition genetic ablation or transgenic over expression of AR modify enal-induced UPR. Using a murine model of coronary occlusion we also plan to study how AR activity and expression levels affect ER stress and UPR during ischemia and reperfusion. We expect that the results obtained from these studies will further our understanding of the nature of ischemic injury and may suggest new ways to prevent tissue injury and dysfunction associated with myocardial infarction. PUBLIC HEALTH RELEVANCE: The aim of this project is to elucidate how ischemia and subsequent reperfusion affects the heart. These studies are of relevance to the understanding of acute myocardial infarction and ischemic heart failure. These diseases are the major cause of death in the U.S. A better understanding of the molecular and cellular mechanisms by which oxidative stress contributes to tissue injury and dysfunction in the ischemic heart may lead to the development of more effective therapeutic interventions to treat heart disease.

project_terms:
Ablation;Acute myocardial infarction;Affect;Aging;Air;Aldehyde Reductase;Aldehydes;Asses;Atherosclerosis;Biochemical Pathway;Biochemical Process;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Death;Cell physiology;Characteristics;Coronary;Coronary Occlusions;Degradation Pathway;Development;Disease;Drug Metabolic Detoxication;Endoplasmic Reticulum;Enzyme Inhibition;Enzymes;Food;Functional disorder;Genetic;Glutathione S-Transferase;Heart;Heart Diseases;Heart failure;In Situ;Inflammation;Inflammatory;Injury;Ischemia;Ischemic Preconditioning;Lead;Ligation;Lipid Peroxidation;Lipids;Mediating;Mediator of activation protein;Metabolism;Modeling;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Nature;Neurodegenerative Disorders;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Phase;Proteins;Proteolysis;Reaction;Reactive Oxygen Species;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Research;Role;Structure;Testing;Therapeutic Intervention;Tissues;Toxic effect;Transgenic Organisms;Water;Work;adduct;aldehyde dehydrogenases;base;biological adaptation to stress;endoplasmic reticulum stress;heart metabolism;insight;lipid metabolism;overexpression;oxidation;oxidized lipid;pollutant;prevent;public health relevance;response


application_id: 7867547
project_number: 3P50DA005312-19S1
project_title: CDART - Center for Drug Abuse Research Translation
administering_ic: NIDA
award_notice_date: 2009-06-15
application_type: 3
activity_code: P50
ic: DA
serial_number: 005312
suffix: S1
program_official: LLOYD, JACQUELINE
project_start_date: 1992-09-30
project_end_date: 2012-06-30
study_section: ZDA1-RXL-E(29)
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The current renewal application for the Center for Drug Abuse Research Translation (CDART) consists of a core and four projects. The central integrated theme of the Center is that reward seeking and inhibition are biologically-based personality constructs associated with drug abuse vulnerability and that these constructs are useful in the design of targeted drug abuse prevention messages. The Core will: (1) provide thematic scientific integration of the different projects around the constructs of reward seeking and inhibition; (2) create synergy across the four proposed projects and other ongoing projects on campus; (3) facilitate interdisciplinary collaboration among 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 practice. In Project 1 (Bardo PI) a laboratory rat model will be used to determine if individual differences in reward seeking and inhibition are associated with stimulant drug self-administration and mesocorticolimbic cellular processes. In Project 2 (Kelly PI) human volunteers will be tested in a controlled laboratory environment to assess if individual differences in reward seeking and inhibition are associated with differences in drug reward and neural function as measured by functional magnetic resonance imaging (fMRI) and electroencephalography (EEC). In Project 3 (Lynam PI) a cohort of students transitioning from high school to college will be used to determine if individual differences in reward seeking and inhibition are associated with the initiation escalation and/or cessation of drug use in a longitudinal design. In Project 4 (Zimmerman PI) formative and experimental research will be conducted to determine if televised anti-drug public service announcements (PSAs) are differentially effective among individuals who vary in reward seeking and inhibition. Thus all of the critical elements are now in place to assess at multiple levels of discipline (biomedicine psychology and health communication) the role of reward seeking and inhibition in drug abuse vulnerability with the long-term goal of improving the efficacy of anti-drug televised PSAs that are tailored specifically for at-risk youth transitioning to adulthood.

project_terms:
Basic Science;Cell physiology;Discipline;Drug abuse;Drug usage;Electroencephalography;Elements;Environment;Functional Magnetic Resonance Imaging;Goals;Health Communication;Human Volunteers;Individual;Individual Differences;Laboratories;Laboratory Rat;Measures;Modeling;Neurophysiology - biologic function;Personality;Pharmaceutical Preparations;Prevention;Psychology;Rewards;Risk;Role;Science;Self Administration;Services;Students;Testing;Translating;Translational Research;Youth;base;cohort;college;design;drug abuse prevention;drug reward;high school;improved;interdisciplinary collaboration;longitudinal design;neurobehavioral;psychosocial;research study;research to practice


application_id: 7865546
project_number: 3R01HL084611-04S1
project_title: Role of the Nuclear Receptor Nor-1 in Atherosclerosis and Vascular Injury
administering_ic: NHLBI
award_notice_date: 2009-08-15
application_type: 3
activity_code: R01
ic: HL
serial_number: 084611
suffix: S1
program_official: SRINIVAS, POTHUR R
project_start_date: 2009-08-15
project_end_date: 2012-07-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8010784
contact_pi: BRUEMMER, DENNIS CHRISTOPHER
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: Y
project_abstract:
DESCRIPTION (provided by applicant): The evolving understanding of mechanisms contributing to the development of atherosclerosis and neointima formation following vascular injury has identified members of the nuclear hormone receptor superfamily as key transcriptional regulators of gene expression programs controlling inflammation and proliferation. Although much attention has focused on the role of the peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) subfamilies the nuclear receptor superfamily comprises a large number of so-called orphan nuclear receptors whose target genes and physiological functions are unknown and remain to be discovered.     The neuron-derived orphan receptor-1 (Nor-1) is a constitutively-active transcription factor belonging to the nuclear hormone receptor superfamily. Our Preliminary Data identified Nor-1 expression in human atherosclerotic lesions and in the developing neointima following vascular injury. In response to growth factor stimulation vascular smooth muscle cells (SMC) rapidly express Nor-1 characterizing this nuclear receptor as an early response gene. Experiments using SMC isolated from Nor-1 deficient mice further reveal that Nor-1 expression is required for SMC proliferation cell cycle progression and telomerase activity.     Based on these findings the central hypothesis of this proposal is that Nor-1 functions as a transcriptional regulator of SMC proliferation and thereby contributes to the development of atherosclerosis and neointima formation following vascular injury.     To test this hypothesis we propose the following aims: Specific Aim 1: To determine the transcriptional regulation of Nor-1 expression in SMC. Specific Aim 2: To determine the molecular mechanisms by which Nor-1 regulates SMC proliferation. Specific Aim 3: To determine the contribution of Nor-1 to the development of atherosclerosis by cross- breeding Nor-1 deficient mice to atherosclerosis-susceptible apoE-deficient mice. Specific Aim 4: To determine the contribution of Nor-1 to neointima formation using a model of guide-wire induced femoral artery injury in Nor-1 deficient mice.     Ultimately these experiments may characterize a novel transcriptional pathway regulating SMC proliferation in vascular disease and identify suppression of the nuclear receptor Nor-1 as a previously unrecognized target for the treatment of cardiovascular diseases.

project_terms:
Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Attention;Blood Vessels;Breeding;Cardiovascular Diseases;Cell Cycle Progression;Cell Proliferation;Data;Development;ERG gene;Failure (biologic function);Figs - dietary;Functional disorder;Gene Expression;Gene Targeting;Growth Factor;Human;Inflammation;Injury;Ligands;Liver;Modeling;Molecular;Mus;Muscle Cells;Neurons;Nuclear;Nuclear Hormone Receptors;Nuclear Orphan Receptor;Nuclear Receptors;Orphan;Pathogenesis;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Physiological;Play;Process;Regulator Genes;Role;Smooth Muscle Myocytes;Telomerase;Testing;Transcriptional Regulation;Treatment Failure;Vascular Diseases;base;femoral artery;member;neointima formation;novel;prevent;programs;receptor;research study;response;restenosis;transcription factor


application_id: 7864561
project_number: 2R56AG019223-06
project_title: Ceramide and acute phase protein elevation during aging
administering_ic: NIA
award_notice_date: 2009-06-18
opportunity_number: PA-07-070
application_type: 2
activity_code: R56
ic: AG
serial_number: 019223
program_official: GUO, MAX
project_start_date: 2001-04-01
project_end_date: 2011-06-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Our lab has long standing interest in the mechanisms leading to the state of chronic
low-grade inflammation which is an intrinsic component of the aging process and many
aging-associated diseases. In the past we reported that the hepatic response to one of
the major inflammatory cytokines Interleukin 1&#946; (IL-1&#946;) is significantly augmented during
aging causing an excessive production of IGFBP1 a secretory hepatic protein that binds
to the Insulin-like Growth Factor 1 (IGF1) and neutralizes its bioactivity. This
hyperresponsiveness is caused by intrinsic activation of neutral sphingomyelinase 2 in
liver and accumulation of its product ceramide an evolutionary conserved second
messenger which mediates cellular stress response. Here we hypothesize that this IL-
1&#946; hyperresponsiveness impairs the insulin signaling pathway in liver. First we will
investigate how aging-associated IL-1&#946; hyperresponsiveness affects the insulin pathway
and will study the interactions between key molecules in the two cascades PI3K Akt-1
and Foxo1 (for insulin) and ceramide IRAK-1 and JNK (for IL-1&#946;). Studies will be done
in isolated hepatocytes in vitro and in animals in vivo. Young aged and aged calorie
restricted rats and mice will be used. The regulation of IGFBP1 promoter by the two
pathways will be investigated in H4IIE cells. These molecular studies will be
complemented by assays of insulin- and IGFBP1-depndent functions in vivo which
include tests of IGF1 bioactivity muscle functions and glucose regulation. Throughout
the experiments cause and effect relations will be tested by overexpression and
silencing approach using adenovirus-mediated gene transfer.
Project

project_terms:
Acute-Phase Proteins;Acute-Phase Reaction;Address;Adenovirus Vector;Adenoviruses;Adult;Affect;Age;Aging;Aging-Related Process;American;Animals;Arthritis;Biological Assay;CCL4 gene;Caloric Restriction;Cardiovascular Diseases;Cell membrane;Cells;Cellular Stress Response;Ceramides;Chronic;Complement;Cytosol;Data;Development;Disease;Distal;Dose;EMSA;Elderly;Elements;Environment;Fatty Acids;Foundations;Funding;Future;Gene Expression;Gene Transfer;Genes;Health;Hepatic;Hepatocyte;Hyperglycemia;Immune response;Impairment;In Vitro;Infection;Inflammation;Inflammatory;Insulin;Insulin Resistance;Insulin Signaling Pathway;Insulin-Like Growth Factor I;Insulin-Like Growth-Factor Binding Protein 1;Interleukin-1;Length;Link;Lipids;Liver;Longevity;Luciferases;MAPK8 gene;Measurement;Mediating;Metabolic;Metabolism;Molecular;Monitor;Mus;Muscle;Muscle function;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Export;Nuclear Extract;Nuclear Translocation;Organism;Pathway interactions;Pattern;Phosphorylation;Phosphotransferases;Physiological;Play;Production;Promotor (Genetics);Protein Binding;Protein Isoforms;Rattus;Regulation;Regulatory Element;Reporter;Reporting;Research;Rodent;Role;Second Messenger Systems;Serum;Signal Pathway;Signal Transduction;Sphingolipids;Sphingomyelinase;System;Tail;Testing;Ubiquitination;Up-Regulation (Physiology);Veins;Wound Healing;Yeasts;age related;aged;base;blood glucose regulation;cytokine;dihydroceramide desaturase;drug maintenance;frailty;glucose tolerance;hepatoma cell;improved;in vivo;insulin receptor substrate 1 protein;insulin sensitivity;insulin signaling;interest;juvenile animal;liver function;long chain fatty acid;muscle strength;overexpression;prevent;receptor;research study;response;sarcopenia;second messenger;small hairpin RNA;tool;transcription factor

public_health_relevance:
Understanding the mechanisms that dysregulate liver functions during aging is
very important for improving the health of older Americans because liver plays critical
role in the clearance of all prescription drugs and the maintenance of overall body
metabolism.


application_id: 7862574
project_number: 5R01HL081525-06
project_title: MAPK/PKR Modulation of Diaphragm Weakness
administering_ic: NHLBI
award_notice_date: 2010-05-12
application_type: 5
activity_code: R01
ic: HL
serial_number: 081525
program_official: SMITH, ROBERT A
project_start_date: 2006-07-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-K(07)M]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
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
budget_start_date: 2010-07-01
project_abstract:
DESCRIPTION (provided by applicant): The respiratory muscles of critically ill patients requiring mechanical ventilation are profoundly weak and infections are a major factor contributing to the development of this debility. The cellular mechanisms by which systemic infection induces respiratory muscle weakness however are poorly understood. In other tissues the effects of infection are mediated by a variety of signaling pathways but virtually nothing is known about the signaling pathways activated in respiratory skeletal muscle in response to infection. The purpose of the experiments in this proposal is to examine this issue. These experiments will test our central hypothesis: p38 JNK and PKR kinase pathways interact to regulate diaphragm muscle death receptor activation death receptor active caspase 8 formation and caspase mediated reductions in diaphragm force generation. Aim I studies will test the hypothesis that p38 and JNK modulate inflammation induced skeletal muscle caspase 8 activation and contractile dysfunction. Studies will be done using mice given endotoxin and C2C12 muscle cells exposed to cytokines. We will examine the time course of activation of p38 and JNK and will also determine if chemical or genetic inhibition of p38 and/or JNK prevents inflammation induced caspase 8 formation and diaphragm weakness. We will also determine if NADPH oxidase mediated superoxide generation causes skeletal muscle p38 and JNK activation in response to inflammation. Aim II studies will test the hypothesis that PKR also contributes to inflammation induced skeletal muscle caspase 8 activation and weakness. We will examine the time course of skeletal muscle PKR activation and will determine if chemical or genetic inhibition of PKR prevents inflammation induced skeletal muscle caspase 8 formation and weakness. We will also determine if PACT/RAX activation is responsible for activating PKR in skeletal muscle following inflammatory stimuli. Aim III studies will test the hypothesis that inflammation induces specific changes in skeletal muscle death receptor complex (DISC) characteristics that are linked to activation of the p38 JNK and PKR signaling pathways. We will both characterize the effects of inflammation on DISC formation localization and autocatalytic activity and determine if these alterations can be blocked by inhibition of p38 JNK and/or PKR signaling pathways.

project_terms:
Animal Model;Animals;Biological Assay;Cartilage;Cell physiology;Cells;Cessation of life;Characteristics;Chemicals;Complex;Contractile Proteins;Critical Illness;Development;Diaphragm (Anatomy);Dominant-Negative Mutation;Double-Stranded RNA;Endotoxins;Environmental air flow;Functional disorder;Generations;Genetic;Hand;Hyperglycemia;In Vitro;Individual;Infection;Inflammation;Inflammatory;Knock-out;Limb structure;Link;MAP Kinase Activation Pathway;MAP Kinase Gene;MAPK14 gene;MAPK8 gene;Measures;Mechanical ventilation;Mediating;Mitogen-Activated Protein Kinases;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Weakness;Muscle function;NADP;NADPH Oxidase;Pathway interactions;Patients;Phosphotransferases;Play;Proteolysis;Proteomics;Protocols documentation;Receptor Activation;Research;Research Personnel;Respiratory Failure;Respiratory Muscles;Role;Secondary to;Sepsis;Signal Pathway;Skeletal muscle structure;Stimulus;Stress;Superoxides;Systemic infection;Techniques;Testing;Time;Tissues;Weaning;Western Blotting;Work;caspase;caspase-3;caspase-8;caspase-9;cell injury;cell type;chemical genetics;cytokine;design;eIF-2 Kinase;inhibitor/antagonist;macrophage;p38 MAPK Signaling Pathway;prevent;programs;receptor;research study;respiratory;response


application_id: 7862396
project_number: 5R01DC002736-13
project_title: Functional Domains and Expression of Olfactory Receptors
administering_ic: NIDCD
award_notice_date: 2010-05-25
application_type: 5
activity_code: R01
ic: DC
serial_number: 002736
program_official: SULLIVAN, SUSAN L
project_start_date: 1995-08-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1-IFCN-K(03)M]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
DESCRIPTION (provided by applicant): The mammalian olfactory epithelium does two remarkable things with its olfactory sensory neurons. These neurons detect odorants translating the structure of volatile chemicals into a neural information code and the epithelium can replace these neurons even if they are completely eliminated. These properties are of significant interest for both basic and applied neuroscience research. The goal of this project is to generate a finely detailed description of the phenotypes of the mature olfactory sensory neurons and their immediate progenitor cells then use this description to predict critical steps in the molecular mechanisms that lead to the genesis of these neurons their ability to detect certain odors and their ability to survive in their exposed position. The first aim of this project combines a system-wide view of gene expression with our ability to purify certain cell types so that we can assign gene expression patterns and the biological processes they represent to their correct homes in the cells of the epithelium. The second aim takes advantage of predictions about genes whose products regulate the activity of other genes made by our preliminary data. We will test whether targeted knockout of six of these regulator genes all expressed by immature olfactory sensory neurons causes deficits in either the production of mature neurons or in critical functions of these neurons. The third aim is based on our belief that within the expression patterns we observe in olfactory sensory neurons are sets of genes responsible for survival of the neurons. We will use odor stimulation which is known to enhance survival to increase the activity of pro-survival genes (or suppress anti-survival genes) so that they can be detected. This project is an integrated approach to understanding the genes whose activity is important for generating the phenotype of mature olfactory sensory neurons and then maintaining these cells in the face of significant challenges.

project_terms:
Abbreviations;Afferent Neurons;Age;Analysis of Variance;Belief;Biological Process;Boxing;Bromodeoxyuridine;Cell Adhesion;Cells;Chemicals;Chronic Lymphocytic Leukemia;Cilia;Code;Data;Defect;Energy Metabolism;Environment;Epithelium;Event;Face;Flagella;Fluorescence-Activated Cell Sorting;Galactosidase;Gel;Gene Expression;Gene Silencing;Gene Targeting;Genes;Genetic Transcription;Germ Cells;Goals;Green Fluorescent Proteins;Growth Associated Protein 43;Home environment;Homeobox;Individual;Ion Transport;Knock-out;LacZ Genes;Lead;Link;Lymphoid;Lymphoma;Maintenance;Measures;Messenger RNA;Molecular;Mus;Myelogenous;Neurons;Neurosciences Research;Odors;Olfactory Epithelium;Pattern;Phenotype;Polymerase Chain Reaction;Population;Positioning Attribute;Production;Property;RNA;Regulation;Regulator Genes;Research Personnel;Reverse Transcription;Signal Transduction;Sorting - Cell Movement;Spermatogenesis;Stem cells;Structure;Synaptic Transmission;System;Testing;Tissues;Translating;base;cell injury;cell type;chromatin remodeling;cilium biogenesis;deprivation;enhanced green fluorescent protein;experience;human ASCL1 protein;interest;knockout gene;leukemia;leukemia/lymphoma;neurogenesis;olfactory marker protein;olfactory receptor;postnatal;precursor cell;progenitor;programs;relating to nervous system;tool;transcription factor


application_id: 7861337
project_number: 1RC2DA028984-01
project_title: Transdermal Cannabinoid Prodrug Treatment for Cannabis Withdrawal and Dependence
administering_ic: NIDA
award_notice_date: 2009-09-30
opportunity_number: RFA-OD-09-004
application_type: 1
activity_code: RC2
ic: DA
serial_number: 028984
program_official: PARK, MOO KWANG
project_start_date: 2009-09-30
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZDA1 JXR-D (9F)]
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L.
other_pis: WEBSTER, LYNN
congressional_district: 06
department: Unavailable
primary_duns: 178031683
primary_uei: EKBZRSBPS8A3
duns_number: 178031683
uei: EKBZRSBPS8A3
fips: US
organization_id: 10006751
organization_name: ALLTRANZ, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Cannabis use disorders affect approximately 1.5% of the United States population and more than half of the individuals addicted to marijuana experience significant withdrawal symptoms if they try to quit which contributes to the relapse and maintenance of marijuana use. AllTranz is seeking funding to create a transdermal delivery system of delta-9-tetrahydrocannabinol (THC) as an adjunct treatment for marijuana withdrawal and dependence. While the approved THC (Marinol) capsule provides potentially effective treatment for cannabis use disorders oral drug delivery is not desirable because of the peak plasma level related side effects and short duration of action. The transdermal system would be a non-invasive non-oral dosage form with ultimate dosing/duration flexibility and also have fewer drug side effects (i.e. no THC plasma peak level related euphoria). Initial positive preliminary data has encouraged AllTranz to seek funding to develop new THC prodrugs and optimize their use through a transdermal drug delivery system. Prodrugs are chemically modified parent drugs that are more skin permeable than the parent and once they cross the stratum corneum quickly separate back into the parent drug and prodrug moiety. Transdermal formulations also provide more abuse deterrence than immediate release dosage forms. Transdermal delivery systems offer a number of improvements over other delivery systems. Patches and gels do not require swallowing eliminating oral side effects and bitter taste concerns; nor do they require skin puncture by needles eliminating pain and patient visits to a physician. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid the first pass effect decreasing gastric side effects and liver damage effects in hepatocompromised drug abusers. Specifically we aim to synthesize skin permeable prodrugs of THC. We then aim to assess their in vitro human skin permeation for optimum flux. The optimal prodrugs will be evaluated for chemical stability and performance in adhesive patch formulations. The best prodrug candidate will undergo synthesis scale-up optimization prototype patches will be manufactured and preclinical toxicology testing will be completed. An IND will be submitted to the FDA so that a Phase I clinical trial can be completed. A proof of concept study in marijuana withdrawal can be completed under this two-year plan. We will create a marketable transdermal drug that will significantly aid in the treatment of marijuana dependence and withdrawal.  
  
PUBLIC HEALTH RELEVANCE: Cannabis use disorders affect approximately 1.5% of the United States population and more than half of the individuals addicted to marijuana experience significant withdrawal symptoms if they try to quit which contributes to the relapse and maintenance of marijuana use. AllTranz is seeking funding to create a transdermal delivery system of THC as an adjunct treatment for marijuana withdrawal and dependence. The transdermal system would be a non-invasive non-oral dosage form with ultimate dosing flexibility and also have fewer drug side effects (i.e. no THC plasma peak level-related euphoria).

project_terms:
Adhesions;Adhesives;Adverse drug effect;Adverse effects;Affect;Back;Blood Circulation;Cannabinoids;Cannabis;Cannabis Abuse;Clinical;Clinical Trials;Data;Deglutition;Dependence;Development Plans;Diffusion;Disease;Dosage Forms;Dose;Drug Addiction;Drug Approval;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Drug abuser;Euphoria;FDA approved;Funding;Gel;Grant;Human;In Vitro;Individual;Investigational New Drug Application;Liver;Maintenance;Marihuana;Marijuana Dependence;Marijuana Smoking;Marketing;Methods;Mouth Diseases;Needles;Oral;Pain;Parents;Pathway interactions;Patients;Performance;Pharmaceutical Preparations;Phase I Clinical Trials;Physicians;Plasma;Population;Prodrugs;Property;Puncture procedure;Relapse;Replacement Therapy;Research;Residual state;Route;Safety;Skin;Stomach;Stratum corneum;System;Taste Perception;Testing;Tetrahydrocannabinol;Time;Toxicology;Transdermal substance administration;United States;Visit;Withdrawal;Withdrawal Symptom;capsule (pharmacologic);chemical stability;chronic pain;clinical effect;design;effective therapy;experience;flexibility;improved;marijuana user;pre-clinical;prototype;public health relevance;scale up

public_health_relevance:
Narrative:Cannabis use disorders affect approximately 1.5% of the United States population and more thanhalf of the individuals addicted to marijuana experience significant withdrawal symptoms if they try toquit which contributes to the relapse and maintenance of marijuana use. AllTranz is seeking fundingto create a transdermal delivery system of THC as an adjunct treatment for marijuana withdrawal anddependence. The transdermal system would be a non-invasive non-oral dosage form with ultimatedosing flexibility and also have fewer drug side effects (i.e. no THC plasma peak level-relatedeuphoria).


application_id: 7860813
project_number: 3R01AA018016-01S1
project_title: The Role of Alcohol in HIV Therapy Hepatotoxicity
administering_ic: NIAAA
award_notice_date: 2009-07-15
opportunity_number: RFA-AA-08-013
application_type: 3
activity_code: R01
ic: AA
serial_number: 018016
suffix: S1
program_official: WANG, JOE
project_start_date: 2009-07-15
project_end_date: 2010-06-30
study_section: ZAA1-BB(02)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: BARVE, SHIRISH S;EATON, JOHN W
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_terms:
Acetaminophen;Acquired Immunodeficiency Syndrome;Acute Liver Failure;Affect;Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Anti-HIV Agents;Anti-HIV Therapy;Anti-Retroviral Agents;CD4 Positive T Lymphocytes;CYP2E1 gene;Caspase Inhibitor;Cause of Death;Chronic;Clinical;Combination Drug Therapy;Combivir;Communicable Diseases;Delavirdine;Development;Didanosine;Disease;Disease Progression;Drops;Drug Interactions;Enrollment;Enzymes;Fatty Liver;Functional disorder;Gilead brand of tenofovir disoproxil fumarate;Goals;Grant;HIV;HIV Infections;HIV therapy;Health;Hepatic;Hepatitis;Hepatitis B Virus;Hepatitis C;Hepatitis C virus;Hepatocyte;Hepatology;Hepatotoxicity;Highly Active Antiretroviral Therapy;Histology;Human;Hypersensitivity;Immune;In Vitro;Incidence;Indinavir;Infection;Injury;Insulin Resistance;Killings;Lactic Acidosis;Lamivudine;Life Expectancy;Lipodystrophy;Liver;Liver diseases;Lopinavir/Ritonavir;Lymphocyte Count;Lymphocyte Depletion;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Morbidity - disease rate;Mortality Vital Statistics;Mus;Names;Nelfinavir;Nevirapine;Nucleosides;Nucleotides;Outcome;Oxidative Stress;Patients;Pharmaceutical Preparations;Pneumonia;Population;Predisposition;Principal Investigator;Production;Protease Inhibitor;Proteasome Inhibition;Proteins;Reaction;Reporting;Research;Reverse Transcriptase Inhibitors;Risk;Ritonavir;Roche brand of pentafuside;Role;S-Adenosylmethionine;Saquinavir;Saquinavir Mesylate;Screening procedure;Series;Severities;Simulate;Site;Stavudine;Symptoms;T-20;TNF gene;Technology;Tenofovir;Testing;Therapeutic Intervention;Time;Toxic effect;Trizivir;Tuberculosis;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;United States National Institutes of Health;Universities;Viral hepatitis;Work;World Health Organization;Zalcitabine;Zidovudine;abacavir;alcohol effect;analog;base;caspase;cohort;crixivan;cytokine;depressed;design;efavirenz;emtricitabine;epivir;experience;feeding;fosamprenavir;high risk behavior;immune function;inhibitor/antagonist;interest;intervention program;mitochondrial dysfunction;multicatalytic endopeptidase complex;non-nucleoside reverse transcriptase inhibitors;novel;programs;prospective;public health relevance;reconstitution;sustiva;tipranavir;translational approach;truvada;viracept

public_health_relevance:
NARRATIVEAlcohol abuse and HIV are important health problems. Liver disease is recognized as anincreasingly important problem for the HIV population. Liver disease may be due to a variety offactors including co-infection with viral hepatitis alcohol abuse and antiretroviral hepatotoxicity.Liver disease is now a leading cause of death for patients with HIV. Hepatoxicity due to HAARTis also common and up to 30% of patients on HAART experience World Health Organizationgrade 3 liver enzyme elevations. Furthermore hepatoxicity from antiretroviral drugs leads toadverse patient outcomes either from fulminant hepatic failure or more commonly AIDSfollowing discontinuation of HAART. It is unknown why some but not all HIV patients developdrug induced liver injury from HAART. Relevant to this proposal alcohol/HAART interactionsare emerging as critically important factors. Recent research has shown that alcohol abuse isassociated with severe hepatotoxicity in patients on HAART. Importantly alcoholic liver diseaseand HAART induced liver injury share many potential mechanisms of injury. These includecytokine dysregulation mitochondrial dysfunction and proteasomal dysfunction. Through theseand other mechanisms alcohol and antiretroviral medications converge on the liver in anoverlapping fashion to produce hepatoxicity. Here we will study hepatotoxicity due toalcohol/HAART interactions to further define disease mechanisms and create therapeuticinterventions.


application_id: 7860667
project_number: 5R01AA016013-02
project_title: Zinc inhibition of endotoxemia in alcoholic liver injury
administering_ic: NIAAA
award_notice_date: 2010-05-24
opportunity_number: PA-07-065
application_type: 5
activity_code: R01
ic: AA
serial_number: 016013
program_official: GAO, PETER
project_start_date: 2009-06-05
project_end_date: 2010-08-01
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 6870954
contact_pi: ZHOU, ZHANXIANG
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: Y
project_abstract:
DESCRIPTION (provided by applicant): Zinc inhibition of endotoxemia in alcoholic liver injury Abstract Alcoholic liver disease (ALD) is an important health problem but an FDA-approved effective therapy is not available. A better understanding of the mechanisms involved in the pathogenesis of ALD will certainly pave the way to develop effective therapies for treating this disease. Several hypotheses regarding the mechanisms by which alcohol induces liver injury have been postulated including ethanol metabolism-generated oxidative stress endotoxemia and proinflammatory cytokine production. Each of the three factors has been shown to contribute significantly to ALD. However the critical trigger for these detrimental events has not been defined. Although previous studies have largely focused on the direct effects of ethanol on the liver clinical evidence indicates that excessive ethanol consumption is necessary but not sufficient to induce liver injury. Gut-derived endotoxin has been suggested as one of the most important cofactors in development of ALD. Endotoxin is known to trigger proinflammatory cytokine production in the liver leading to inflammation oxidative stress and eventually cell death. While endotoxemia is well documented in patients with ALD the mechanisms involved in the development of endotoxemia have not been fully understood. Given the fact that only alcoholics with gut leakiness develop ALD intestinal barrier dysfunction is likely the cause of endotoxemia. Therefore suppression of endotoxemia by sealing the leaky gut could be very an attractive approach for treating ALD. Our previous studies have shown that inhibition of endotoxemia is associated with zinc prevention of acute ethanol-induced liver injury. Importantly our preliminary data identify a novel potential mechanism by which ethanol and zinc regulate the intestinal barrier. We found that zinc deficiency and dysfunction of zinc finger transcription factors disrupt the barrier function of Caco-2 cells through depressing junction proteins. In this context we hypothesize that zinc homeostasis plays a critical role in regulation of intestinal barrier function. We will carry out the following specific aims and research approaches in this project. Aim 1 will determine the role of zinc deficiency in the pathogenesis of ethanol-induced intestinal barrier dysfunction and endotoxemia. A chronic ethanol exposure rat model will be utilized to induce alcoholic endotoxemia. First we will determine disturbance of intestinal zinc homeostasis in association with ethanol-induced intestinal barrier dysfunction and endotoxemia. Second the impact of zinc deficiency on intestinal barrier function and the possible synergistic action with ethanol will be determined by using a dietary zinc deficiency model. We expect the results of Aim 1 to demonstrate that zinc deprivation is a causal factor in the pathogenesis of ethanol-induced intestinal barrier disruption. Aim 2 will investigate the molecular mechanisms by which zinc deficiency interferes with intestinal barrier function. Caco-2 cell culture model will be utilized to determine whether ethanol-induced zinc deficiency lead to dysfunction of zinc finger transcription factors and whether zinc finger transcription factors critically regulate epithelial barrier structure and function. We will first define the links between ethanol-induced ROS generation and zinc mobilization and depression of zinc finger transcription factors. We will then define the role of zinc finger transcription factors in regulation of tight junction proteins and barrier function by gene silencing and expression. We expect Aim 2 to demonstrate that zinc mobilization from zinc finger transcription factors is a critical molecular event in ethanol-induced epithelial barrier disruption. Aim 3 will evaluate the beneficial effect of dietary zinc supplementation on ethanol-induced gut leakiness and endotoxemia. A chronic ethanol exposure rat model will be utilized to evaluate the beneficial effects of dietary zinc supplementation on ethanol-induced intestinal leakiness and the consequent endotoxemia and hepatitis. We expect that dietary zinc supplementation through preserving zinc finger transcription factors will seal the leaky gut and attenuate endotoxemia and the consequent hepatitis. These studies will provide novel insights into the role of zinc in modulation of ethanol-induced gut leakiness and the consequent endotoxemia and hepatitis. The results would have high potential leading to a simplistic approach to prevention/treatment of ALD.

project_terms:
Acute;Alcohol consumption;Alcoholic Liver Diseases;Attenuated;Caco-2 Cells;Cell Culture Techniques;Cell Death;Chronic;Clinical;Data;Depressed mood;Development;Dietary Zinc;Disease;Endotoxemia;Endotoxins;Epithelial;Ethanol;Ethanol Metabolism;Event;FDA approved;Functional disorder;Gene Silencing;Generations;Health;Hepatitis;Homeostasis;Inflammation;Injury;Intestines;Lead;Link;Liver;Mental Depression;Modeling;Molecular;Oxidative Stress;Pathogenesis;Patients;Play;Prevention;Prevention approach;Principal Investigator;Production;Proteins;Rattus;Regulation;Research;Role;Structure;Supplementation;Tight Junctions;Zinc;Zinc Fingers;Zinc deficiency;abstracting;alcohol effect;alcohol exposure;cofactor;cytokine;deprivation;effective therapy;insight;novel;problem drinker;programs;public health relevance;seal;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alcoholic liver disease is a common health problem. Although much progress has been made in understanding the pathogenesis of Alcoholic liver disease effective therapies are lacking. Although previous studies have largely focused on the direct effects of ethanol on the liver clinical evidence indicates that excessive ethanol consumption is necessary but not sufficient to induce liver injury. Gut-derived endotoxin has been suggested as one of the most important cofactors in development of alcoholic liver disease. Endotoxin is known to trigger proinflammatory cytokine production in the liver leading to inflammation oxidative stress and eventually cell death. While endotoxemia is well documented in patients with alcoholic liver disease the mechanisms involved in the development of endotoxemia have not been fully understood. Given the fact that only alcoholics with gut leakiness develop alcoholic liver disease intestinal barrier dysfunction is likely the cause of endotoxemia. Therefore suppression of endotoxemia by sealing the leaky gut could be very an attractive approach for treating AL alcoholic liver disease.


application_id: 7860364
project_number: 5R01GM085302-02
project_title: Enzyme Mis-Metallation Consequences and Opportunities
administering_ic: NIGMS
award_notice_date: 2010-06-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 085302
program_official: FABIAN, MILES
project_start_date: 2009-07-01
project_end_date: 2012-06-30
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 1896479
contact_pi: MILLER, ANNE-FRANCES
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: Y
project_abstract:
Aerobic organisms exploit O2 to extract large amounts of energy from oxidativemetabolism of food and employ oxidative reactions for a number of important chemicaltransformations involved in antibiotic biosynthesis metabolism of xenobioticsconstruction of biopolymers and more. In order to access this chemistry O2 must beactivated and this is often accomplished via Fe-containing enzymes. Free activated O2reacts with many components of cells and the damage that ensues contributes to manydiseases including diabetes arthritis neurodegenerative conditions cancer and thesymptoms of old age. A crucial biochemical defense against this array of ills is theenzyme superoxide dismutase (SOD) which catalyzes conversion of the parentactivated O2 species superoxide to O2 + H2O2. The current work focuses on theEscherichia coli SOD that is evolved to use Fe as its catalytic metal ion (FeSOD) withsupporting in-vivo experiments on a homologous yeast SOD that employs Mn instead(MnSODSc). The yeast enzyme is highly homologous to the human mitochondrialMnSOD and thus serves as a model for the human enzyme while also drawing onextensive genetic and physiological studies of yeast which cannot be performed onhumans. The major thrusts address mechanisms by which the Fe of FeSOD (and byextension the Fe of O2- activation enzymes) interacts with activated O2 withoutsuccumbing to it and means by which the active site of FeSOD tunes the reactivity of Fe(such that it will de-activate superoxide). The efforts on yeast SOD initiate investigationsof possible pathological consequences of Fesubstitution into human SOD via the yeastmodel and test a mutation by which this pathology could be prevented or corrected. Themajor thrust builds directly on past research in the applicant's lab using E. coli FeSODvariants that have been shown to be trapped in one of the two states employed byFeSOD's catalytic cycle but to retain otherwise native-like active sites. Because theycannot progress through the catalytic cycle they are ideal systems in which to generatemodels of enzyme-substrate and enzyme-product complexes to learn how the FeSODactive site binds and interacts with its substrate and products. Detailed studies by skilledspectroscopists as well as mechanistic and thermodynamic studies will provide anexceptionally complete picture of models of the intermediates of SOD turnover andinsights into how Fe enzymes handle their essential but dangerous substrate.Established enzymological and biophysical approaches will be blended with stopped-flow and freeze-quenched methods to extend the lab's ability to treat short-livedcomplexes. The yeast system will be launched. Initial studies of the reactions betweenperoxide and Fe-substituted MnSOD will evaluate the potential significance of Fesubstitution into SOD to human oxidative stress. A mutation developed in E. coli andcharacterized as part of the mechanistic work will also be tested for ability to reverse thepossible toxic effects of Fe substitution into yeast MnSOD thus carrying translatingmechanistic insights into potential treatments.

project_terms:
Active Sites;Address;Aerobic;Age;Aging;Alzheimer's Disease;Anabolism;Antibiotics;Antioxidants;Arthritis;Assimilations;Binding (Molecular Function);Biochemical;Biopolymers;Carbohydrates;Cell Respiration;Chemicals;Chemistry;Commuting;Complex;Coupled;Degenerative Disorder;Diabetes Mellitus;Disease;Electron Transport;Enzyme Activation;Enzymes;Escherichia coli;Fermentation;Food;Free Radicals;Freezing;Genetic;Heme Oxygenase (Decyclizing);Human;Hydrogen Peroxide;Intercept;Investigation;Ions;Iron;Learning;Life;Malignant Neoplasms;Manganese;Manganese Superoxide Dismutase;Metabolism;Metals;Methods;Micronutrients;Mitochondria;Modeling;Mutation;Nature;Nerve Degeneration;Organism;Oxidative Stress;Oxygen;Parents;Pathology;Peroxides;Physiological;Production;Proteins;Protons;Reaction;Research;Saccharomyces cerevisiae;Side;Sideroblastic Anemia;Site;Specificity;Stream;Stress;Structure;Superoxide Dismutase;Superoxides;Symptoms;System;Testing;Thermodynamics;Time;Toxic effect;Translating;Variant;Work;Xenobiotic Metabolism;Yeast Model System;Yeasts;analog;base;cell injury;enzyme substrate;experience;gain of function;human SOD2 protein;in vivo;insight;oxidative damage;portability;prevent;research study

public_health_relevance:
Humans cannot survive without using oxygen yet oxygen's side reactions make major contributions to thesymptoms and progress of diverse conditions including diabetes arthritis neurodegeneration cancer andAlzheimer's disease as well as 'old age'. The proposed research addresses the crucial connection betweenthe micronutrients iron and manganese and efficient metabolism of oxygen and seeks to explain why incorrectassimilation of iron can contribute to the oxygen-fuelled degenerative conditions above.


application_id: 7858469
project_number: 5R01HL082791-05
project_title: Vascular Smooth Muscle Hyper-contractility and Hypertension in Type-II-Diabetes
administering_ic: NHLBI
award_notice_date: 2010-05-14
application_type: 5
activity_code: R01
ic: HL
serial_number: 082791
program_official: OLIVE, MICHELLE
project_start_date: 2006-06-01
project_end_date: 2013-05-31
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-06-01
project_abstract:
DESCRIPTION (provided by applicant): Sixteen million Americans have type II diabetes and vascular complications are the most common causes of morbidity and mortality in diabetic patients. Abnormalities in blood vessel constriction or dilatation (vasomotion) detected in early diabetes can result in blood flow dysregulation and increased peripheral resistance thereby contributing to diabetic complications. We and others found that db/db and high fat diet-induced type II diabetic mice are hypertensive and vascular smooth muscle tissues isolated from these animals exhibit a significantly increased contractile response to stimuli. However the molecular mechanisms are unknown. In preliminary studies we observed that Ca2+sensitization of contractions are significantly increased in vascular smooth muscle tissues isolated from type II diabetic mice. We found that CPI-17 PKCbetall RhoA and ROCK four key players of Ca2+ sensitization signaling are significantly up-regulated/ activated in diabetic arteries. Moreover inhibiting PKC or ROCK diminished the enhanced Ca2+ sensitization of contractions in vascular smooth muscle tissue isolated from db/db mice. Therefore we hypothesize that in type II diabetes activated PKCbetall and RhoA/ROCK activate CPI-17 and thereby significantly contribute to type II diabetic vascular smooth muscle hyper-contractility and hypertension. Specific aims are: (1) To test the hypothesis that activation of CPI-17 is responsible for enhanced Ca2+ sensitization and vascular smooth muscle hyper-contractility in db/db and diet-induced type II diabetic mice. (2) To test the hypothesis that the activation of PKCbetall and RhoA/ROCK are required for vascular smooth muscle hyper-contractility in db/db and diet-induced type II diabetic mice. (3) To test the in vivo significance of the CPI-17 in vascular smooth muscle hyper-contractility and type II diabetes-associated hypertension by using pharmacological and genetic approaches. Both in vitro and in vivo methods will be employed. Isolated small mesenteric arteries will be used to investigating isometric contractions Ca2+ sensitization of contractions the mRNA protein and activities of CPI-17 RhoA/ROCK and PKC. In addition blood pressure will be measured in mice by using radiotelemetry and carotid artery catheter. The proposed study may provide new insight into the molecular mechanisms of vascular smooth muscle dysfunction in type II diabetes and into the pathogenesis of diabetes-associated hypertension.

project_terms:
Agonist;American;Animals;Arteries;Binding (Molecular Function);Blood Pressure;Blood Vessels;Blood flow;Cardiovascular Diseases;Carotid Arteries;Catheters;Complications of Diabetes Mellitus;Data;Development;Diabetes Mellitus;Diabetic Angiopathies;Diabetic Retinopathy;Diabetic mouse;Diet;Dilatation - action;Endothelium;Exhibits;Fatty acid glycerol esters;Functional disorder;GTP-Binding Proteins;Genetic;Goals;Hypertension;In Vitro;Isometric Contraction;Kidney Diseases;Measures;Mesenteric Arteries;Messenger RNA;Methods;Molecular;Molecular Weight;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle Contraction;Muscle Smooth Vascular;Neuropathy;Non-Insulin-Dependent Diabetes Mellitus;Pathogenesis;Peripheral Resistance;Phosphoric Monoester Hydrolases;Physiological;Play;Protein Kinase C;Proteins;Regulation;Research Personnel;Rho-associated kinase;Role;Scheme;Signal Pathway;Signal Transduction;Smooth muscle (tissue);Stimulus;Testing;Transgenic Mice;Up-Regulation (Physiology);Vascular Smooth Muscle Tissue;Vasospasm;Work;constriction;db/db mouse;diabetic;diabetic patient;in vivo;inhibitor/antagonist;insight;myosin phosphatase;new therapeutic target;programs;response;vasomotion


application_id: 7858439
project_number: 5R21AG029907-02
project_title: Neprilysin and Peripheral Clearance of Amyloid Peptides
administering_ic: NIA
award_notice_date: 2010-05-12
opportunity_number: PAS-06-261
application_type: 5
activity_code: R21
ic: AG
serial_number: 029907
program_official: SUNEJA, SANOJ
project_start_date: 2009-06-15
project_end_date: 2012-05-31
study_section: Special Emphasis Panel[ZRG1-MNPS-C(09)F]
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
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: Y
project_abstract:
DESCRIPTION (provided by applicant): It has been shown that peripheral clearance of amyloid beta peptides reduces amyloid beta peptide levels in the brain through what has been termed a "sink effect". We have exploited this "sink effect" by showing that the peptidase neprilysin when expressed peripherally on leukocytes reduced amyloid beta peptide levels in the brain of a hAPP transgenic mouse model of Alzheimer's disease. To obtain peripheral neprilysin expression we transplanted bone marrow stem cells transduced with lentivirus expressing neprilysin to a recipient hAPP transgenic mouse. We now propose to further develop peripheral expression of neprilysin as a therapeutic treatment for AD. Two specific aims directed at further developing peripheral neprilysin expression without the need for bone marrow transplantation are proposed: SPECIFIC AIM 1. To test the use of a single chain antibody-neprilysin (NEP) chimeric protein targeted to red blood cells to lower brain amyloid beta peptide levels. Chimeric proteins composed of a single chain antibody targeted to a mouse erythrocyte epitope fused with neprilysin will be used to produce erythrocyte bound neprilysin which will be tested for the ability to lower brain amyloid beta peptide levels. SPECIFIC AIM 2. To test the use of a myristoylated-neprilysin to attach NEP to hematopoietic cells. We will generate a form of neprilysin in which a myristoyl-peptide is linked to the C-terminus. This myristoyl-NEP will be used to produce peripheral NEP by insertion into the plasma membrane of hematopoietic cells and tested for the ability to lower brain amyloid beta peptide levels. We have as an overall objective the translation of one of these methods to the testing of human subjects. PUBLIC HEALTH RELEVENCE: The focus of this proposal is to develope a new therapeutic approach for treating Alzheimer's disease. We propose to express the enzyme neprilysin on blood cells where it can degrade plasma amyloid beta peptides leading to a lowering of brain amyloid beta peptides which are known to play a major role in causing Alzheimer's disease.

project_terms:
Abeta clearance;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Antibodies;Binding (Molecular Function);Blood;Blood Cells;Blood Platelets;Bone Marrow Cells;Bone Marrow Stem Cell;Bone Marrow Transplantation;Brain;Cell membrane;Cell surface;Cells;Chimera organism;Chimeric Proteins;Complement;Enzymes;Epitopes;Erythrocytes;Ganglioside GM1;Gelsolin;Hematopoietic;Human;Hydrolysis;Impaired cognition;Injection of therapeutic agent;Leukocytes;Link;Lymphocyte;Measures;Methods;Mus;Neprilysin;Peptide Hydrolases;Peptides;Peripheral;Plasma;Play;Principal Investigator;Proteins;Role;Subfamily lentivirinae;Tail;Testing;Therapeutic;Transgenic Mice;Translations;Transplantation;Veins;amyloid peptide;human subject;immunogenicity;morris water maze;mouse model;novel therapeutic intervention;prevent;programs;public health medicine (field)


application_id: 7858335
project_number: 5R01AI068119-05
project_title: Do Condoms Protect From Non-Viral Sexually Transmitted Infections?
administering_ic: NIAID
award_notice_date: 2010-05-26
application_type: 5
activity_code: R01
ic: AI
serial_number: 068119
program_official: DAVID, HAGIT S
project_start_date: 2006-06-15
project_end_date: 2013-05-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
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 PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-06-01
project_abstract:
DESCRIPTION (provided by applicant): A recent federal report suggested that rigorous tests of condom effectiveness against sexually transmitted infections (STIs) are urgently needed. 1 To date published studies have not described tests of condom effectiveness. Further a search of the CRISP database revealed that studies of condom effectiveness have not yet been funded. The proposed study uses an innovative approach to testing condom effectiveness against penile-vaginal acquisition of a) Chlamydia b) trichomoniasis and c) any of three non-viral STIs (Chlamydia trichomoniasis and gonorrhea) (Aim 1). The negative sequelae of these infections are well documented. The infections also increase the odds of HIV acquisition and transmission. Because the protective value is highly likely to vary between men and women the study will also test for moderating effects of sex (gender) on condom effectiveness (Aim 2). Based on a substantial amount of research conducted by the PI of the proposed study it is also quite apparent that various forms of condom failure must be accounted for in tests of condom effectiveness. Therefore the study will quantify the loss of protective value attributable to these sources of failure (Aim 3). A final study aim is to determine the loss of protective value incurred as the frequency of condom use decreases from 100% (Aim 4). The sample will be 625 men and 625 women (> 15 years of age) attending one of two clinics for the evaluation and treatment of an STI. Participants will be followed over 6 months. After initially being tested (using DNA amplification) and treated (using single-dose directly observed therapy) for existing non-viral STIs participants will learn how to use a Personal Digital Assistant to keep an electronic coital diary over the subsequent 6 months. This innovative method of data collection helps assure optimal validity of the assessed behaviors. A brief education session will also be provided. This session will promote the correct and consistent use of condoms during the study period thereby helping to ensure that an adequate number of participants are classified as "100%" users in the analyses. A 3-month follow-up screening will detect early reinfections or new infections. A 6-month follow-up period will also include re-screening for the three STIs. The study is adequately powered (> 80%) to detect even modest effect sizes. Findings will be disseminated to inform public health policy and programs related to the use of condoms in the prevention of these common non-viral STIs.

project_terms:
15 year old;Accounting;Address;American;Behavior;Chlamydia;Chlamydia trachomatis;Clinic;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;DNA amplification;Data Collection;Databases;Directly Observed Therapy;Dose;Educational aspects;Educational workshop;Effectiveness;Electronics;Ensure;Evaluation;Event;Failure (biologic function);Federal Government;Female;Frequencies (time pattern);Funding;Gender;Gonorrhea;HIV;Health Policy;Human Papillomavirus;Incidence;Infection;Investigation;Journals;Laboratories;Latex;Learning;Male Condoms;Methods;Neisseria gonorrhoeae;Outcome;Participant;Patient Self-Report;Personal Digital Assistant;Policies;Porosity;Prevention;Prevention program;Prophylactic treatment;Prospective Studies;Published Comment;Publishing;Relative (related person);Reporting;Research;Research Design;Research Personnel;Risk;Risk Reduction;Sampling;Screening procedure;Sexually Transmitted Diseases;Source;Syphilis;Systematic Bias;Tail;Testing;Trichomonas Infections;Trichomonas vaginalis;United States Dept. of Health and Human Services;Vagina;Viral;Woman;base;cohort;condoms;consistent condom use;design;diaries;follow-up;genital herpes;innovation;male;men;prevent;programs;prospective;public health medicine (field);sex;sound;transmission process


application_id: 7857987
project_number: 5R01DE019645-02
project_title: Devices for Treating Inflammatory Bone Loss in an Oral Environment
administering_ic: NIDCR
award_notice_date: 2010-05-06
opportunity_number: PA-07-279
application_type: 5
activity_code: R01
ic: DE
serial_number: 019645
program_official: LUMELSKY, NADYA L
project_start_date: 2009-06-01
project_end_date: 2013-02-28
study_section: Musculoskeletal Tissue Engineering Study Section[MTE]
contact_pi_person_id: 1874927
contact_pi: PULEO, DAVID A.
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: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  An association between infection and suboptimal regenerative outcomes has often been described in the periodontal and oral surgical literature. It is also increasingly recognized that low-level bacterial contamination can play a role in "aseptic" loosening of total joint implants. In this context the term "infection" does not refer to fulminating acute processes but to subclinical indolent infections characterized by colonization of substrates. In these conditions microbial contaminants initiate synthesis of potent pro-inflammatory cytokines by local cells. These primary mediators in turn stimulate production of secondary mediators that amplify the inflammatory response. The end result is secretion of tissue-degrading enzymes and eventually osteoclastic bone resoprtion. In this project a multidisciplinary team approach will be used to develop proactive multifunctional devices for localized bone regeneration in sites compromised by oral microbes by attacking the problems of microbial contamination inflammation tissue destruction and hindered tissue repair. In Aim 1 a controlled release system for sequential delivery of multiple biomolecules will be developed. With respect to this Aim it is hypothesized that the devices can be tailored to deliver antibacterial anti-inflammatory anticatabolic and anabolic compounds with discrete profiles that ensure appropriate bioactivity. In Aim 2 devices selected from Aim 1 will be investigated for their ability to control microbial bioburden and inflammation as well as to inhibit bone resorption and to promote bone formation in vitro and material degradation and drug release will be correlated with in vivo findings. It is hypothesized that biomolecules released from the devices will kill oral microbes decrease osteoclastic differentiation/activity and increase osteoblastic differentiation/activity. In Aim 3 complete devices providing individual sequential combined and simultaneous drug release profiles will be tested for their biological activity in vivo using a canine peri- implantitis model. It is hypothesized that sequential treatment of the different phases of the disease process with a unitary device will be more effective than the common approach of treating only one of the components. The findings of these studies will contribute to understanding of the chain of biological events that occurs during bacterially-induced inflammatory bone destruction and they will progress the field of biomedical device development toward more effective means for enhancing bone regeneration in an oral microbial environment. PUBLIC HEALTH RELEVANCE: Colonization of natural and synthetic biomaterials by bacteria elicits a cascade of local tissue reactions that ultimately lead to loss of the supportive structures. Such tissue destruction is at the heart of many conditions including infected teeth bones dental implants and joint implants. This project will develop multifunctional unitary controlled release devices that halt the detrimental processes and stimulate localized tissue repair in sites compromised by bacteria.

project_terms:
Acute;Acute suppurative arthritis due to bacteria;Affect;Anti-Bacterial Agents;Anti-Inflammatory Agents;Anti-inflammatory;Antibiotics;Bacteria;Biocompatible Materials;Biological;Bone Regeneration;Bone Resorption;Canis familiaris;Catabolic Process;Cells;Connective Tissue;Cyst;Data;Defect;Dental;Dental Implants;Development;Device or Instrument Development;Devices;Disease;Effectiveness;Ensure;Environment;Enzymes;Event;Goals;Heart;Human;Implant;In Vitro;Individual;Indolent;Infection;Inflammation;Inflammatory;Inflammatory Response;Joints;Killings;Kinetics;Lead;Light;Literature;Location;Mediator of activation protein;Mesenchymal;Methods;Microbe;Modeling;Natural regeneration;Operative Surgical Procedures;Oral;Oral cavity;Organism;Orthopedics;Osteoblasts;Osteoclasts;Osteogenesis;Osteolysis;Osteomyelitis;Outcome;Periodontitis;Pharmaceutical Preparations;Phase;Play;Pluronics;Polymers;Process;Production;Property;Reaction;Role;Sequential Treatment;Site;Structure;Surface;System;Testing;Tissues;Tooth structure;Ursidae Family;Work;Wound Healing;antimicrobial;bactericide;base;bone;bone loss;cellulose acetate phthalate;combat;connective tissue metabolism;controlled release;cytokine;design;implantable device;in vivo;microbial;multidisciplinary;osteoblast differentiation;particle;peri-implantitis;progenitor;public health relevance;regenerative;repaired;soft tissue;tissue regeneration;treatment strategy

public_health_relevance:
Project NarrativeColonization of natural and synthetic biomaterials by bacteria elicits a cascade of local tissue reactions thatultimately lead to loss of the supportive structures. Such tissue destruction is at the heart of many conditionsincluding infected teeth bones dental implants and joint implants. This project will develop multifunctionalunitary controlled release devices that halt the detrimental processes and stimulate localized tissue repair insites compromised by bacteria.


application_id: 7857725
project_number: 3R01DC007194-04S2
project_title: Genomic of Olfactory Regeneration
administering_ic: NIDCD
award_notice_date: 2009-07-17
application_type: 3
activity_code: R01
ic: DC
serial_number: 007194
suffix: S2
program_official: DAVIS, BARRY
project_start_date: 2009-07-17
project_end_date: 2010-10-31
study_section: Special Emphasis Panel[ZRG1-IFCN-K(03)M]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
The sensory neurons of the olfactory epithelium can be regenerated even if they are completely eliminated.This capacity lasts throughout the life of the animal and is of significant interest for both basic and appliedneuroscience research. Its mechanisms are presumed to be relevant to the search for regeneration-promoting therapies for neurodegenerative disorders and trauma of the nervous system. Its mechanismsare also clearly relevant to neural development. To extend our understanding of olfactory regeneration wehave identified 1205 mRNAs whose abundance within the olfactory epithelium changes after removal of theolfactory bulbs a manipulation that causes the selective death and subsequent regeneration of the olfactorysensory neurons. Of these mRNAs 303 increase contemporaneously with the proliferation of sensoryneuron progenitors. The functions of the proteins encoded by these 303 mRNAs predict several underlyingprocesses including transcriptional activation of cell proliferation and differentiation up-regulation of the cellcycle axon outgrowth and cell signaling. Only a handful of these proteins have previously been linked toolfactory regeneration or development. In this application we propose to focus on a subset of gene productsthat are likely to be critical for proliferation and differentiation of the olfactory sensory neurons. The firstspecific aim is to define the capacity for each gene product to be involved in olfactory regeneration bydetermining which cell types express them including spatial and temporal overlap with markers of knownprogenitor cell types. The second and third aims focus further on a subset of genes for which targeteddeletions are available. These aims test whether the absence of the gene alters the development orregeneration of the olfactory epithelium leading to changes at the cellular or molecular level. The proposedexperiments will definitively test whether several proteins are dispensable for olfactory development andregeneration and will define the potential roles of a couple dozen additional proteins.

project_terms:
Abbreviations;Adult;Affect;Afferent Neurons;Analysis of Variance;Animals;Axon;Basal Cell;Cell Cycle;Cell Proliferation;Cells;Cessation of life;Data Set;Development;Differentiation and Growth;Embryo;Erinaceidae;Excision;Fibroblast Growth Factor;Fluorescent in Situ Hybridization;Galactosidase;Genes;Genomics;Green Fluorescent Proteins;Growth Associated Protein 43;Helix-Turn-Helix Motifs;Knockout Mice;LacZ Genes;Life;Link;Measures;Messenger RNA;Methods;Molecular;Mouse Strains;Mus;Natural regeneration;Nervous System Trauma;Neurodegenerative Disorders;Neurons;Neurosciences Research;Odorant Receptors;Olfactory Epithelium;Pattern;Play;Polymerase Chain Reaction;Process;Proteins;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Reverse Transcription;Role;Series;Signal Transduction;Signaling Protein;Stem cells;Testing;Time;Transcript;Transcription factor genes;Transcriptional Activation;Up-Regulation (Physiology);Work;cell type;human ASCL1 protein;interest;mutant;neurodevelopment;neurogenesis;neuron development;null mutation;olfactory bulb;olfactory marker protein;postnatal;progenitor;programs;protein function;receptor expression;research study;response;sustentacular cell;transcription factor


application_id: 7856018
project_number: 3R01AA017226-03S1
project_title: Alcohol and Breast Cancer
administering_ic: NIAAA
award_notice_date: 2009-07-14
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: AA
serial_number: 017226
suffix: S1
program_official: JUNG, KATHY
project_start_date: 2009-07-15
project_end_date: 2010-06-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
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
project_abstract:
Project Summary/Abstract
Alcoholism alcohol abuse and the medical complications of excessive drinking are major
world-wide health problems. Alcohol is a tumor promoter. Epidemiological studies indicate that
heavy alcohol consumption increases risk of breast cancer and is associated with advanced and
invasive breast tumors. However the etiology of alcohol-induced tumor promotion is elusive.
Cellular/molecular mechanisms underlying alcohol-promoted tumor development and
progression remain unknown. ErbB2 a member of the epidermal growth factor receptor
tyrosine kinase family is frequently over-expressed in human breast cancers. We have
demonstrated that alcohol dramatically promotes migration/invasion of mammary epithelial cells
and breast cancer cells over-expressing ErbB2. We also reveal that the human transmembrane
mucin (MUC1) is highly sensitive to alcohol. a-catenin is a proto-oncogene and plays an
important role in tumorigenesis and cancer progression. The E-cadherin/a-catenin complex a
critical component of cell-cell adherens maintains the integrity of epithelial cell interactions and
regulates cell migration/invasion. We propose a novel role of MUC1 as an adaptor protein that
bridges ErbB2 and a-catenin and facilitate ErbB2/a-catenin interaction and the dissociation of Ecadherin/
a-catenin complex. Our central hypothesis is that ethanol-induced oxidative stress upregulates
MUC1 as an adaptor protein to promote ErbB2/a-catenin interaction which induces
dissociation of the a-catenin/E-cadherin complex leading to cell transformation and cell
migration/invasion. Both in vitro and in vivo models will be utilized to test this novel hypothesis.
Specific Aim 1 will establish the pivotal role of MUC1 in ethanol-promoted ErbB2/a-catenin
interaction. Specific Aim 2 will determine whether ethanol-promoted cell transformation and
cancer cell migration/invasion is mediated by MUC1-dependent dissociation of the Ecadherin/
a-catenin complex. Specific Aim 3 will investigate in vivo effects of ethanol. We will
investigate the effect of ethanol on mammary tumorigenesis/metastasis in MMTV-Neu
transgenic mice. We will further investigate the effect of ethanol on the interactions among
MUC1 ErbB2 a-catenin and E-cadherin as well as the role of ROS and MUC1 in ethanolmediated
tumorigenesis/metastasis in the transgenic and nude mice. As a cohesive unit the
multi-disciplinary approaches using in vitro and in vivo models will systematically explore the
mechanisms underlying alcohol-promoted tumorigenesis and malignant progression of breast
cancer. The study will elucidate a novel function of ErbB2 and MUC1 in alcohol-induced tumor
promotion. The expression/activity of ErbB2 and MUC1 is frequently aberrant in many other
human cancers and in a variety of human diseases; their levels are also developmentally
regulated. Understanding the interactions among alcohol ErbB2 and MUC1 will also provide an
important insight into the pathogenesis of some human diseases related to alcohol abuse as
well as alcohol?s teratogenic effect during development

project_terms:
Adaptor Signaling Protein;Adult;Alcohol abuse;Alcohol consumption;Alcoholism;Alcohols;American;Animal Model;Animal Welfare;Bibliography;Breast Cancer Cell;Cell Communication;Cell-Cell Adhesion;Cells;Cellular Structures;Complex;Country;Development;Disease;Dissociation;E-Cadherin;ERBB2 gene;Environment;Environmental Impact;Epidemiologic Studies;Epidermal Growth Factor Receptor;Epithelial Cells;Equipment;Esophagus;Ethanol;Etiology;Family;Future;Genus Cola;Goals;Health;Heavy Drinking;Human;IACUC;In Vitro;International;Larynx;Literature;Liver;Malignant - descriptor;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Medical;Membrane;Molecular;Mucin-1 Staining Method;Mucins;Neoplasm Metastasis;Nude Mice;Oral cavity;Organ;Outcome;Ovary;Oxidative Stress;Pathogenesis;Patients;Pharyngeal structure;Phosphorylation;Play;Principal Investigator;Protein Tyrosine Kinase;Proto-Oncogenes;Reactive Oxygen Species;Rectum;Research;Research Ethics Committees;Research Personnel;Resources;Risk;Role;Stomach;Testing;Therapeutic;Transgenic Mice;Transgenic Organisms;Tumor Promoters;Tumor Promotion;United States;Up-Regulation (Physiology);Vertebrates;abstracting;alcohol effect;alcohol related problem;cancer cell;cancer risk;carcinogenesis;cell motility;cell transformation;cellular targeting;chronic alcohol ingestion;cost;expiration;human disease;human subject;in vivo;in vivo Model;insight;malignant breast neoplasm;medical complication;member;migration;novel;problem drinker;programs;tumor;tumor progression;tumorigenesis


application_id: 7855756
project_number: 1R25CA148005-01
project_title: The Development of an Interdisciplinary Oncology Palliative Care Curriculum
administering_ic: NCI
award_notice_date: 2010-09-01
opportunity_number: PAR-08-120
application_type: 1
activity_code: R25
ic: CA
serial_number: 148005
program_official: LEI, MING
project_start_date: 2010-09-01
project_end_date: 2015-08-31
study_section: Education Study Section (G)[NCI-G]
contact_pi_person_id: 8126973
contact_pi: PFEIFER, MARK P
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): In 2010 cancer is expected to surpass heart disease as the highest health-related cause of mortality in the world. Almost every family has or will face a loved one needing cancer care including curative treatment symptom control and end-of-life care. The increasing needs of our patient population and the emerging science of palliative care call for new efforts in innovative education. National organizations have called for new efforts in interdisciplinary understanding and education in approaching palliative care. Each discipline however has continued to teach palliative care principles largely in silos using existing curricular structure and constructs; there are no reports of mandatory interdisciplinary education in palliative care involving all four disciplines - medicine nursing social work and chaplaincy.   
  
The aim of this project is to design implement and evaluate an innovative integrated and interdisciplinary oncology palliative care curriculum for medical nursing social work and chaplaincy students.   
  
Specific aims are:   
1) Design an innovative interdisciplinary oncology palliative care curriculum;   
2) Implement the interdisciplinary oncology palliative care curriculum;   
3) Develop and utilize an evaluation system that measures the effectiveness of the curriculum learner outcomes and the long term impact on practitioners and patients.   
  
Project efforts will focus the design implementation and testing of an interdisciplinary oncology palliative care curriculum. Innovative as well as proven education modalities will be utilized to determine:   
1) If the educational objectives are aligned with the desired outcomes;   
2) Which modalities are most effective for each discipline?   
3) How the modalities are best integrated; and   
4) What factors contribute to the sustainability and portability of the curriculum.   
  
The new curriculum will include eight learning activities that will become a required part of the curriculum for all 3rd year medical students 3rd and 4th year nursing students masters level social work students and clinical pastoral education residents. In addition to traditional educational modalities such as clinical rotations didactic sessions and self-study modules non-traditional methods including standardized patients and families reflective writing a palliative care vignette case-solving and capstone projects will be used. The added value of interdisciplinary education will be evaluated in this field.  
  
PUBLIC HEALTH RELEVANCE: Almost every family has or will face a loved one needing cancer care including curative treatment symptom control and end-of-life care. In receiving this care patients and their families will need the services of physicians nurses chaplains and social workers. The Institute of Medicine lists working in interdisciplinary teams as one of five core competencies all health care clinicians should possess and calls for health professionals to be educated in an interdisciplinary manner to prepare them for the real world team environments they will participate in once entering the field. This project will create implement and test a novel mandatory interdisciplinary oncology palliative care curriculum for medical nursing social work and chaplaincy students.

project_terms:
Address;Adult;Awareness;Cancer Control;Cancer Patient;Caring;Clinical;Communities;Development;Discipline;Discipline of Nursing;Educational Curriculum;Educational aspects;Educational process of instructing;End of Life Care;Environment;Evaluation;Face;Family;Guidelines;Health Professional;Health Sciences;Healthcare;Heart Diseases;Institute of Medicine (U.S.);Knowledge;Learning;Malignant Neoplasms;Mandatory Reporting;Medical;Medical Students;Medicine;Methods;Modality;Mortality Vital Statistics;NIH Program Announcements;Nurses;Nursing Students;Outcome;Palliative Care;Patient Care;Patients;Physicians;Rotation;Science;Services;Social Workers;Social work (field);Structure;Students;Symptoms;System;Technology;Testing;Training;Translating;United States National Institutes of Health;Work;Writing;cancer care;career;clinical practice;design;effectiveness measure;evidence base;experience;flexibility;innovation;loved ones;novel;oncology;patient population;portability;programs;public health relevance


application_id: 7854387
project_number: 1RC2GM092521-01
project_title: Advancing Drug Development from Medicinal Plants using Transcriptomics and Metabo
administering_ic: NIGMS
award_notice_date: 2009-09-30
opportunity_number: RFA-OD-09-004
application_type: 1
activity_code: RC2
ic: GM
serial_number: 092521
program_official: JONES, WARREN
project_start_date: 2009-09-30
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZGM1 PPBC-X (TR)]
contact_pi_person_id: 8279550
contact_pi: CHAPPELL, JOE
other_pis: DELLAPENNA, DEAN ;O'CONNOR, SARAH E
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Medicinal plants produce a wealth of pharmaceutical compounds such as taxol vincristine and morphine. Unfortunately the specialized secondary metabolic pathways leading to such compounds remain poorly understood and progress in elucidating and manipulating these taxonomically restricted metabolic pathways has been correspondingly slow. This has been exacerbated by the limited development of "omics"-level resources for medicinal plants which has meant that as a group research in medicinal species have not benefited to the same extent from the genomics revolution as have research in model plants and agronomic crop species. This proposal describes the combined use of state-of-the-art sequencing technologies metabolomics capabilities and bioinformatics to develop an unrestricted public resource to address this growing gap in our knowledge base of species-specific plant metabolism and accelerate the identification and functional analysis of genes involved in natural product biosynthesis in 20 widely used medicinal plant species. This resource will provide the research community with user-friendly access to the DNA sequences and expression profiles of each plant's transcriptome and associated metabolome which we anticipate will have a translational effect on drug development. To achieve this goal we will utilize next generation sequencing approaches to determine the near-complete set of mRNAs encoded by each medicinal plant species. Transcriptome profiling of up to 20 chemically diverse tissues/treatments per species using the RNA-Seq method from Illumina will be performed and correlated with metabolite profiles generated through LC-TOF and GC-MS for these same samples. All sequence and gene expression data will be deposited into NCBI and made available along with metabolite profiling data at medicinalplantgenomics.msu.edu a custom website developed by the research consortium. Thus this NIH Grand Opportunities Grant will provide searchable and downloadable databases for medicinal plant gene sequences expression profiles and metabolites that can be accessed and utilized by the research community to facilitate discovery of the pathways and genes responsible for biosynthesis of key pharmaceuticals. High throughput sequencing of genomes and transcriptomes has revolutionized and accelerated the pace and progress of research across the life sciences and this proposal will for the first time extend these advances into the medicinal plant arena on a broad scale.  
PUBLIC HEALTH RELEVANCE: This proposal describes the combined use of state-of-the-art DNA sequencing technologies metabolomics capabilities and bioinformatics to develop an unrestricted public resource to advance our knowledge base of species-specific plant metabolism and accelerate the identification and functional analysis of genes involved in natural product biosynthesis in 20 widely used medicinal plant species. This resource will provide the research community with user-friendly access to the DNA sequences and expression profiles of each plant's transcriptome and associated metabolome which we anticipate will have a translational effect on drug development.

project_terms:
Address;Agricultural Crops;Aliquot;Anabolism;Animal Model;Arabidopsis;Arts;Bioinformatics;Biological Factors;Biological Sciences;Bone callus;Communities;Custom;DNA Sequence;Data;Data Set;Databases;Deposition;Development;Flowers;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Genes;Genome;Genomics;Goals;Grant;Health;Human;Knowledge;Libraries;Link;Maize;Maps;Medicinal Plants;Messenger RNA;Metabolic;Metabolic Pathway;Metabolism;Methods;Molecular Profiling;Morphine;Organism;Paclitaxel;Pathway interactions;Pharmacologic Substance;Plant Genes;Plant Leaves;Plant Model;Plant Roots;Plants;Process;Production;Quality Control;RNA;Reading;Relative (related person);Research;Resources;Rice;Sampling;Sorghum (Plant);Technology;Time;Tissue Sample;Tissues;Titanium;Transcript;United States National Institutes of Health;Variant;Vincristine;Work;biological research;candidate identification;drug development;gene function;genome sequencing;improved;insight;knowledge base;metabolomics;next generation;novel;public health relevance;stem;tool;transcriptomics;user-friendly;virtual;web site

public_health_relevance:
NarrativeThis proposal describes the combined use of state-of-the-art DNA sequencingtechnologies metabolomics capabilities and bioinformatics to develop anunrestricted public resource to advance our knowledge base of species-specificplant metabolism and accelerate the identification and functional analysis ofgenes involved in natural product biosynthesis in 20 widely used medicinal plantspecies. This resource will provide the research community with user-friendlyaccess to the DNA sequences and expression profiles of each plant'stranscriptome and associated metabolome which we anticipate will have atranslational effect on drug development.


application_id: 7853954
project_number: 3R01DC007176-05S1
project_title: Neurotrophin regulation of taste system development
administering_ic: NIDCD
award_notice_date: 2009-07-17
application_type: 3
activity_code: R01
ic: DC
serial_number: 007176
suffix: S1
program_official: SULLIVAN, SUSAN L
project_start_date: 2009-07-17
project_end_date: 2010-12-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
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: Y
project_abstract:
DESCRIPTION (provided by applicant): During development gustatory innervation is a tightly regulated process in which specific numbers of primary taste afferents project to discrete regions of the oral cavity. The present research is designed to investigate gustatory innervation in support of two long terms goals: 1) to determine the cellular and molecular mechanisms that allow gustatory neurons to innervate the correct target (taste buds) with a specific mount of innervation and 2) to determine if and/or how these connections are important for central gustatory development or taste function. The proposed project focuses on the role of neurotrophins in regulating gustatory neuron number and peripheral and central targeting during embryonic development. It is known that the number of gustatory ganglion neurons that will exist at birth to innervate taste buds on the tongue and palate is somehow determined by brain-derived neurotrophic factor (BDNI0 and neurotrophin-4 (NT4). However the mechanism(s) by which BDNF and NT4 regulate innervation are unknown and could involve any number of different developmental processes during numerous different embryonic stages. The proposed studies combine in situ hybridization cell counting tract tracing immunohistochemistry and SEM in gene knockout mice to: 1) determine when and where the embryonic taste system is exposed to BDNF and NT4 2) determine when BDNF and NT4 regulate gustatory neuron number and whether this regulation is accomplished by reducing proliferation or by increasing cell death 3) determine whether BDNF and/or NT4 is required for initial target invasion and 4) determine if BDNF and/or NT4 regulate the central distribution of tongue and palatal sensory afferents. Together these studies test the hypotheses that: 1) NT4 is expressed along gustatory fiber projection pathways and regulates gustatory neuron survival before initial innervation of peripheral and central targets and 2) BDNF is expressed in gustatory epithelia and regulates neuron survival after initial peripheral and central target innervation. Because these experiments examine how neurotrophins regulate the amount and location of sensory innervation this project has important implications for the potential therapeutic use of these powerful signaling molecules in controlling neural regeneration following injury.

project_terms:
Afferent Neurons;Axon;Biological Assay;Birth;Brain-Derived Neurotrophic Factor;Bromodeoxyuridine;Cell Count;Cell Cycle;Cell Death;Cessation of life;Computer Systems Development;Development;Developmental Process;Embryo;Embryonic Development;Epithelium;Fiber;Fungiform Papilla;Future;Ganglia;Genes;Genotype;Goals;Growth;Hybrids;Immunohistochemistry;In Situ Hybridization;Injury;Knockout Mice;Knowledge;Label;Location;Maintenance;Mediating;Microscopy Electron Scanning;Molecular;Mus;Myxoid cyst;Nerve Fibers;Nerve Regeneration;Neurites;Neuronal Differentiation;Neurons;Nucleus solitarius;Oral cavity;Palate;Pathway interactions;Pattern;Peripheral;Process;Regulation;Research;Role;Sensory;Sensory Ganglia;Signal Pathway;Signaling Molecule;Staging;Structure of geniculate ganglion;System;Taste Buds;Taste Perception;TdT-Mediated dUTP Nick End Labeling Assay;Testing;Therapeutic Uses;Time;Tongue;Withdrawal;axon regeneration;design;ganglion cell;nerve supply;neural circuit;neuron development;neuron loss;neurotrophic factor;neurotrophin 4;postnatal;postsynaptic;receptor;research study;response;synaptogenesis;tongue papilla


application_id: 7853857
project_number: 3R01EY014701-04S2
project_title: GABAc Receptors & Mouse Retinal Ganglion Cell Responses
administering_ic: NEI
award_notice_date: 2009-07-14
application_type: 3
activity_code: R01
ic: EY
serial_number: 014701
suffix: S2
program_official: GREENWELL, THOMAS
project_start_date: 2004-02-01
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-VISC(01)Q]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Vision requires the integration of many aspects of the visual field into a cohesive whole that is used by the organism to navigate its environment. The mammalian retina is a laminar structure and each layer is populated by several cell types that combine to define the response properties of the retinal ganglion cells (RGCs) which transmit the signal to the brain. The many aspects of the visual scene are encoded by two parallel pathways within the retina that either detect increases or decreases in light intensity. There are many types of RGCs and their responses are defined by the inputs they receive. One key element in shaping their response properties is inhibition which like other regions of the brain is mediated by glycine and gamma amino butyric acid (GABA). GABA inhibition is mediated by three receptors GABAA GABAB and GABAC all of which are present in the retina. One challenge then is to determine how each of these inhibitory and excitatory inputs shapes the responses of the RGCs. A new tool towards attaining this goal is the ability to manipulate the mouse genome and selectively remove specific inputs the effect of which then can be assessed on the RGCs. However unlike the extensive literature for cat rabbit and primate relatively little is known about the fundamental properties of murine RGCs. The goal of this proposal is to characterize the response properties of mouse RGCs both in vivo and in vitro and in particular determine the role that GABACR-mediated input plays in shaping the responses. The specific aims are (1) to determine the effect of eliminating genetically GABACR-mediated inhibition on a subset of RGC response properties recorded in vivo and (2) correlate structure and function of a diverse set of RGCs and determine the impact of eliminating GABACR-mediated input on the response properties of each of these cell types. These data will enhance our understanding of the role of inhibition in shaping the response of the output cells of the retina and therefore important aspects of integration of information in the visual field.

project_terms:
Agonist;Biological Models;Brain;Brain region;Butyric Acids;Cells;Cellular Morphology;Complement;Data;Environment;Evaluation;Eye;Feedback;Felis catus;Glycine;Goals;Goldfish;In Vitro;Indium;Individual;Knockout Mice;Knowledge;Light;Literature;Mediating;Morphology;Mus;Nerve Fibers;Optic Nerve;Organism;Oryctolagus cuniculus;Output;Pathway interactions;Physiological;Play;Preparation;Primates;Property;Relative (related person);Reporting;Retina;Retinal;Retinal Ganglion Cells;Role;Salamander;Sampling;Shapes;Signal Transduction;Specificity;Structure;Systems Analysis;Vision;Visual;Visual Fields;cell type;defined contribution;in vivo;interest;light intensity;mouse genome;receptor;response;retinal adaptation;theories;tool;visual receptive field


application_id: 7852205
project_number: 3R01AA003624-30S1
project_title: Control of drug and ethanol metabolism
administering_ic: NIAAA
award_notice_date: 2009-07-13
opportunity_number: PA-05-074
application_type: 3
activity_code: R01
ic: AA
serial_number: 003624
suffix: S1
program_official: GENTRY, THOMAS
project_start_date: 2009-07-15
project_end_date: 2010-12-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): We have identified a novel potential mechanism by which alcohol causes liver damage. Specifically we showed that hepatic expression of plasminogen activator inhibitor-1 (PAI-1) is upregulated by ethanol and the level of expression correlates with protection against liver damage in enteral alcohol model. Furthermore we showed that PAI-1-/- mice are protected against not only fatty liver due to alcohol but also later stages of the disease (inflammation necrosis and fibrosis). We therefore hypothesize that PAI-1 upregulation plays a causal role in ALD. We will build on this hypothesis via the following specific aims. 1) Is PAI-1 involved in enteral alcohol-induced liver injury in mice? We will directly test this hypothesis by investigating the effect of inhibition of PAI-1 expression on liver damage due to alcohol in the enteral mouse model. Specific subhypotheses to be tested are: a) Absence of PAI-1 will protect against experimental ALD in mice b) PAI-1 mediates steatosis after alcohol via impaired VLDL synthesis c) PAI-1 mediates hepatic inflammation during chronic alcohol exposure via fibrin deposition. 2. To determine the mechanism(s) by which PAI-1 is induced by alcohol. The purpose of this specific aim is to identify the major mechanisms by which PAI-1 is induced by chronic alcohol. Specific subhypotheses to be tested are: a) TNFa is the major inducer of PAI-1 due to ethanol. b) PAI-1 is induced by alcohol via mechanisms involving impaired hepatic insulin signaling. 3) To determine the mechanism(s) by which PAI-1 mediates hepatic fibrosis we will build on Preliminary Studies testing the hypothesis that PAI-1 also plays a causal role in hepatic fibrosis. Specific subhypotheses to be tested are: a) PAI-1-/- mice are protected against hepatic fibrosis at the level of matrix resolution b) Matrix metalloproteases are required for enhanced matrix resolution in PAI-1-/- mice c) Inhibition of PAI-1 will enhance recovery from established fibrosis and cirrhosis. Taken together we expect the results of this work to identify a new causal role of PAI-1 in alcoholic liver injury at the level of early damage (steatosis inflammation and necrosis) as well as in later stages of the disease (i.e. fibrosis and cirrhosis). We therefore expect that the results of this work will identify targeting PAI-1 as a new potential therapy for ALD.

project_terms:
A Mouse;Acute;Alcohol consumption;Alcoholic Liver Diseases;Alcoholic liver damage;Alcohols;Chronic;Cirrhosis;Clinic;Clinical Treatment;Deposition;Disease;Drug Controls;Enteral;Ethanol;Ethanol Metabolism;Fatty Liver;Fibrin;Fibrosis;Genetic;Health;Hepatic;Human;Individual;Inflammation;Knowledge;Ligation;Liver;Liver Fibrosis;Mediating;Metalloproteases;Metformin;Modeling;Mus;Necrosis;Pathway interactions;Plasminogen Activator Inhibitor 1;Play;Population;Prevention;Process;Recovery;Relative (related person);Research Personnel;Resolution;Rodent Model;Role;Staging;Steatohepatitis;Testing;Up-Regulation (Physiology);Very low density lipoprotein;Work;alcohol exposure;bile duct;fibrogenesis;hepatic necrosis;insulin signaling;liver transplantation;mouse model;novel;prevent;programs


application_id: 7852204
project_number: 3R01ES011314-05S2
project_title: Arsenic Induced Miotic Arrest Associated Apoptosis
administering_ic: NIEHS
award_notice_date: 2009-07-11
application_type: 3
activity_code: R01
ic: ES
serial_number: 011314
suffix: S2
program_official: THOMPSON, CLAUDIA L
project_start_date: 2009-06-01
project_end_date: 2009-10-31
study_section: Alcohol and Toxicology Subcommittee 1[ALTX-1]
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: Y
project_abstract:
DESCRIPTION (provided by applicant): Arsenic is a natural contaminant of drinking water in many parts of the world is a known human carcinogen and is #1 on the EPA list of hazardous chemicals. Cancers most often associated with chronic arsenism are squamous and basal cell carcinomas of the skin. How arsenic causes cancer is unknown. However the National Research Council Report on Arsenic in Drinking Water concluded that the most likely mode of action is induction of numerical and structural chromosomal abnormalities. Arsenite the carcinogenic form of arsenic found in drinking water disrupts mitosis causing an anaphase delay and induces aneuploidy in normal diploid human fibroblasts and peripheral blood lymphocytes and mitotic arrest associated apoptosis (MAAA) in p53 deficient human fibroblasts. The sensitivity of p53 deficient human cells to arsenite induced MAAA suggests that the mechanism of arsenite carcinogenesis is different than sunlight induced skin carcinogenesis in which p53 mutation is an early and common event. The hypothesis to be investigated is that p53 relieves the arsenite-induced anaphase block by activation of the G2 checkpoint response which inactivates cyclin B/cdc2 and derepresses the mitotic exit network and allow the cells to escape arsenite induced MAAA. It is the prevention of apoptosis in arsenic intoxicated cells that allows genetic instability (aneuploidy) after mitotic disruption. Identification of the cellular factors that interact with p53 or the p53 regulated genes to prevent mitotic arrest associated apoptosis and to allow cells to proceed through mitosis with a delay will provide valuable information regarding the mode of action of arsenite. The specific aims proposed are: 1.) Determine activation of the G2 checkpoint pathway in p53(+) and p53(-) cells arrested by arsenite in mitosis; 2.) Test by overexpression and targeted knockdown of G2 checkpoint proteins the role of G2 checkpoint activation in the escape from arsenite induced anaphase block; 3.) Test whether arsenic associated skin tumors are p53 wild type or mutant. The results of these studies will identify players mediating release from arsenite induced mitotic arrest and will provide valuable information on the mechanism of arsenic induced carcinogenesis clues to the usefulness of arsenite as a chemotherapeutic agent and valuable information on the mode of action of mitosis disrupting drugs in killing human cells.

project_terms:
Anaphase;Aneuploidy;Apoptosis;Arsenic;Arsenites;Basal cell carcinoma;Cancer Etiology;Carcinogens;Cells;Chronic;Cyclin B;DNA;Data;Diploidy;Event;Exons;Fibroblasts;Genes;Genetic;Genomics;Hazardous Chemicals;Human;Individual;Killings;Malignant Neoplasms;Mediating;Messenger RNA;Mitosis;Mitotic;Mitotic Checkpoint;Monitor;Mutation;National Research Council (U.S.);PTCH gene;Pathway interactions;Peripheral Blood Lymphocyte;Pharmaceutical Preparations;Play;Prevention;Proteins;Reporting;Role;Skin;Skin Carcinogenesis;Skin Neoplasms;Structural Chromosomal Abnormality;TP53 gene;Telomerase;Testing;Tetanus Helper Peptide;Tetracyclines;Time;UV induced;cancer cell;carcinogenesis;chemotherapeutic agent;cytotoxicity;drinking water;genetic regulatory protein;mutant;neoplastic cell;overexpression;prevent;protein expression;response;sunlight-induced;tumor;vector


application_id: 7851283
project_number: 5R01DA013930-08
project_title: Redesign of Butyrylcholinesterase for Cocaine Metabolism
administering_ic: NIDA
award_notice_date: 2010-05-04
application_type: 5
activity_code: R01
ic: DA
serial_number: 013930
program_official: SHIH, MING L
project_start_date: 2003-08-20
project_end_date: 2014-05-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
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
budget_start_date: 2010-06-01
project_abstract:
DESCRIPTION (provided by applicant): This project focuses on the rational redesign of human butyrylcholinesterase (BChE) in order to accelerate cocaine metabolism in human. Enhancing cocaine metabolism by administration of BChE has been recognized as a promising treatment strategy for cocaine abuse. However the catalytic activity of this plasma enzyme is three orders-of-magnitude lower against the naturally occurring (-)-cocaine than that against the relatively biologically inactive (+)-cocaine isomer. The primary goal of this project in the previous funding cycle was to understand the mechanistic difference between BChE-catalyzed hydrolyses of (-)- cocaine and (+)-cocaine and to test whether a computational approach works or not for rational design of BChE mutants with an improved catalytic efficiency against (-)-cocaine. Progress on the project has revealed the fundamental catalytic pathways for BChE-catalyzed hydrolyses of (-)-cocaine and (+)-cocaine. We have further developed a novel computational design strategy based on transition state simulation leading to discovery of several BChE mutants with significantly improved catalytic efficiency against (-)-cocaine compared to all BChE mutants reported in literature. Taking advantage of this promising design strategy and protocol in the next phase of the project we propose an integrated computational-experimental effort to further improve the catalytic efficiency of BChE against (-)-cocaine. The proposed integrated computational- experimental approach will include a large-scale virtual screening of a variety of hypothetical BChE mutants based on the transition-state modeling and simulation followed by more sophisticated computational evaluation and wet experimental tests. The Specific Aims include: 1. To determine the detailed reaction coordinates and the corresponding free energy profiles for (-)-cocaine hydrolysis catalyzed by the known high-activity mutants of BChE discovered in the previous funding cycle. 2. To design and discover new BChE mutants with further improved catalytic efficiency against (-)-cocaine by using an extended computational design approach based on the transition state modeling and simulation to evaluate a large number of hypothetical BChE mutants followed by wet experimental tests including site-directed mutagenesis protein expression and catalytic activity assay. The long-term objective of this investigation will be to eventually develop an efficient anti-cocaine medication using a high-activity BChE mutant.

project_terms:
Binding (Molecular Function);Biological Assay;Butyrylcholinesterase;Clinic;Cocaine;Cocaine Abuse;Cocaine Dependences;Coupled;Enzymes;Evaluation;Free Energy;Funding;Goals;Human;Hybrids;Hydrolysis;Investigation;Isomerism;Literature;Mechanics;Metabolism;Microscopic;Modeling;Molecular;Mutation;Neuraxis;Overdose;Pathway interactions;Pharmaceutical Preparations;Phase;Plasma;Process;Protocols documentation;Reaction;Relative (related person);Reporting;Screening procedure;Simulate;Site-Directed Mutagenesis;Structure;Testing;Work;addiction;base;cocaine overdose;cocaine use;computer studies;design;enantiomer;enzyme substrate;improved;models and simulation;mutant;novel;protein expression;quantum;simulation;three dimensional structure;treatment strategy;virtual


