MID ATLANTIC HEART FAILURE NETWORK
P Thomas
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 1U10HL110338-01 from National Heart, Lung, And Blood Institute
Abstract: This is an application from the University of Pennsylvania School of Medicine to participate in the Heart Failure Clinical Research Network (HF-CRN) as a regional clinical center (RCC) and as a Clinical Research Skills Development Core. Our Mid-Atlantic RCC includes Johns Hopkins University and the Lancaster Heart Group. As a composite, our sites follow a demographically diverse population of more than 6,000 patients with heart failure (HF), with more than 1,900 new referrals, 18,000 outpatient visits and 2,900 HF hospitalizations annually. The size and diversity of the existing HF patient population and referral base served by our sites will enable our RCC to identify and enroll patients in virtually any type of HF clinical research study. With this application, we propose a novel clinica trial examining the therapeutic efficacy of recombinant glucagon-like peptide (GLP-1) in patients with severe systolic HF. Recognizing that recent studies demonstrate a 30% rate of death or re-hospitalization and the failure of multiple in-hospital interventions, our study couples the logistical advantages of in-hospital enrollment with the need for a post- hospitalization intervention. The therapeutic promise of GLP-1 is based on the hypothesis that the failing heart is challenged bioenergetically and date indicating that myocardial insulin resistance is high among both diabetics and non-diabetics with severe systolic HF. Small published studies demonstrating that GLP-1 improves myocardial performance and outcomes in patients with systolic dysfunction associated with chronic heart failure, acute myocardial infarction and coronary bypass grafting further support the safety and potential efficacy of GLP-1. Each of these trials was led by Dr. Richard Shannon, the Chairman of Medicine at Penn, who will serve as a consultant for this application. In 360 randomized patients, the proposed study will examine the effect of GLP-1 on the primary endpoint of death or recurrent hospitalization and several secondary endpoints including myocardial contractile reserve assessed via dobutamine stress echocardiography, 6-minute walk distance, quality of life. This novel study of GLP-1 in a high risk population is well-suited to the organization and strength of the HF-CRN. RELEVANCE (See instructions) Heart failure is a leading cause of mortality in the U.S. that imposes a major public health and financial burden. Patients hospitalized with HF are at particular risk for poor outcomes. By evaluating promising clinical interventions, including glucagon-like peptide (GLP-1), this proposal to establish a new regional clinical center for the NHLBI Heart Failure Network will help improve the care of patients with heart failure
Keywords: Accounting; Acute myocardial infarction; Adherence (attribute); Adult; Affect; Aftercare; Age; American; base; Basic Science; Biological Availability; Brain natriuretic peptide; Cardiomyopathies; Cessation of life; Chairperson; Chronic; Clinical; Clinical Research; Clinical Trials; clinically relevant; Community Practice; Complement; Coronary; Coronary Artery Bypass; Couples; Death Rate; design; Development; Devices; diabetic; Diagnosis; Dobutamine; Dobutamine Stress Echocardiography; Dose; Double-Blind Method; Drug Delivery Systems; Effectiveness; Employee Strikes; Enrollment; experience; Faculty; Failure (biologic function); Functional disorder; Future; glucagon-like peptide; glucagon-like peptide 1; Health Care Costs; Heart; Heart failure; Heart Valve Diseases; Hemoglobin; high risk; Hospitalization; Hospitals; improved; Industry; Inpatients; insight; Institution; Instruction; Insulin Resistance; Intervention; Laboratory Study; Lead; Leadership; Levosimendan; Life; Location; Measures; medical schools; Medicine; Metabolic; Milri; Minnesota; Modeling; Mortality Vital Statistics; Multicenter Trials; Myocardial; National Heart, Lung, and Blood Institute; non-diabetic; novel; Outcome; Outcome Measure; Outpatients; Patient Care; patient population; Patients; Pennsylvania; Performance; Phase; Pilot Projects; Placebos; Plasma; Population; Population Heterogeneity; Prevalence; primary outcome; Principal Investigator; pro-brain natriuretic peptide (1-76); Productivity; public health medicine (field); Publishing; Pump; Quality of life; Quality-of-Life Assessment; Randomized; Recombinants; Recurrence; Research; Research Design; research study; Resources; response; Rest; Risk; Rural; Safety; Schedule; secondary outcome; Series; Site; Site Visit; skills; standard care; Structure; subcutaneous; Suburban Population; success; Syndrome; Systolic heart failure; Testing; Therapeutic; tolvaptan; Training; Translational Research; Treatment Efficacy; United States; Universities; Videoconferences; Videoconferencing; Visit; Walking; web site; Weight
Project start date: 2012-01-01
Project end date: 2018-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
1U10HL110338-01 (2012): $370237
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to P Thomas
INJECTABLE COLLAGEN CROSSLINK AUGMENTATION FOR DEGENERATIVE DISC DISEASE
P Thomas, Chief Scientific Officer/associate Profe
Orthopeutics, Lpcity: Lexington country: United States (us)
Grant 5R44AR055014-03 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: With regard to prevalence and cost to society, low-back pain has few peers. With a patient population in excess of 15 million/year, the societal cost is estimated to be in the realm of $100 billion/year. Current treatment options for this disease have shown limited success, including physical therapy, medication and surgery. This proposal involves a novel, nonsurgical and cost-effective, tissue revitalization approach which shows promise for treatment of mechanically and nutritionally challenged tissues like the spinal disc. Previous in vitro and in vivo studies have demonstrated the efficacy of Injectable collagen crosslink augmentation in stabilizing spinal joints, decreasing disc bulge under load, increasing the strength, tear resistance, and durability of the tissue, while also improving nutritional flow to these largely avascular tissues. Phase I testing was successful in characterizing the crosslinking effects of seven candidate agents in disc annulus fibrosis (AF) tissue using mechanical, thermal and protease digestion assays. At least one preferred agent was identified, and concentration, pH, conditioning, and buffering were optimized to maximize the efficiency of crosslinking and mechanical effect. Recently, in vitro assays have been undertaken to determine agent and buffer biocompatibility. The proposed Phase II testing will provide data necessary for regulatory filings and first-in-man clinical trials. Reagent delivery, penetration, reaction kinetics, permanency (effect duration), and storage requirements (shelf life) will be thoroughly investigated. Acute, functional biocompatibility and neurotoxicity studies will be conducted to quantify expected and worst-case treatment effects in an animal model. Further characterization of crosslinking effects will be determined using different subgroups of human AF tissues (variations in age, composition, degeneration). By bringing this path-breaking treatment to the doorstep of clinical trials, SBIR funding will play a vital role in enabling progress towards the ultimate goal of providing a novel, cost-effective treatment in the struggle against low back pain and disability. Back pain and disability associated with spinal degeneration and instability remains among the most costly and prevalent health problems in the US today. With a patient population in excess of 15 million/year, the societal cost is estimated to be in the realm of $100 billion/year. Due to the limited success of current treatment options, it is reasonable to expect that an effective nonsurgical solution could revolutionize clinical care for this pandemic
Keywords: Acute; Address; Age; aged; Animal Model; Animal Models and Related Studies; Animals; Articulation; Assay; Back Ache; Back Pain; Backache; base; Bifunctional Reagents; Bioassay; biocompatibility; Biologic Assays; Biological Assay; biomaterial compatibility; Blood Chemical Analysis; blood chemistry; Body Tissues; bovid; bovine; Bovine Species; Buffers; Cattle; Cell-Extracellular Matrix; Chemical Analyses, Blood; Chemicals; Chromatography, High Performance Liquid; Chromatography, High Pressure Liquid; Chromatography, High Speed Liquid; Clinical; clinical care; clinical investigation; Clinical Trials; Clinical Trials, Unspecified; Collagen; Common Rat Strains; conditioning; cost; cost effective; cow; cross-link; Cross-Linking Reagents; crosslink; Crosslinker; Crosslinking Reagents; Data; design; designing; Digestion; disability; Disease; disease/disorder; Disorder; Drug Formulations; drug/agent; Drugs; ECM; effective therapy; Effectiveness; efficacy testing; Esteroproteases; Extracellular Matrix; Fatigue; Fibrosis; Formulation; Formulations, Drug; Funding; Future; Goals; Health; High Pressure Liquid Chromatography; HPLC; Human; Human, General; improved; In Vitro; in vitro Assay; in vivo; Injectable; Injection of therapeutic agent; Injections; Intervertebral Disc Degenerative Disease; Intervertebral Disc Degenerative Disorder; Intervertebral disc structure; Intervertebral Disk; intervertebral disk degeneration; Investigation; Joints; Kinetic; Kinetics; Lack of Energy; Life; Low Back Ache; Low Back Pain; Low Backache; Lumbago; Mammals, Rats; man; Man (Taxonomy); man`s; Man, Modern; Mechanics; Medication; model organism; Modeling; Modification; Neurologic; Neurological; neuron toxicity; neuronal toxicity; neurotoxicity; novel; Nutritional; Operation; Operative Procedures; Operative Surgical Procedures; pandemic; pandemic disease; patient population; peer; Penetration; Peptidases; Peptide Hydrolases; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Physiatric Procedure; Physical Medicine Procedure; Physical Therapeutics; Physical therapy; Physical Therapy Procedure; Physical Therapy Techniques; Physiotherapy; Physiotherapy (Techniques); Physiotherapy Procedure; Play; Preparation; Prevalence; prevent; preventing; programs; Programs (PT); Programs [Publication Type]; Proteases; Proteinases; Proteolytic Enzymes; public health relevance; Rat; Rattus; Reaction; reaction rate; Reagent; Resistance; resistant; response; Role; SBIR; SBIRS (R43/44); Small Business Innovation Research; Small Business Innovation Research Grant; social role; Societies; Solutions; Spinal; Structure; Subcutaneous Injections; SUBGP; Subgroup; success; surfactant; surgery; Surgical; Surgical Interventions; Surgical Procedure; Testing; Tissues; treatment effect; Variant; Variation
Relevance: Back pain and disability associated with spinal degeneration and instability remains among the most costly and prevalent health problems in the US today. With a patient population in excess of 15 million/year, the societal cost is estimated to be in the realm of $100 billion/year. Due to the limited success of current treatment options, it is reasonable to expect that an effective nonsurgical solution could revolutionize clinical care for this pandemic
Project start date: 2007-08-15
Project end date: 2012-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-09-080
5R44AR055014-03 (2011): $359441
MICHIGAN INSTITUTE FOR CLINICAL AND HEALTH RESEARCH (MICHR) (UL1)
P Thomas, Director, Peds Critical Care
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5UL1RR024986-05 from National Center For Research Resources
Abstract: The University of Michigan Clinical and Translational Sciences Award (UM CTSA) will focus the formidable strengths of one of the world´s finest research institutions on supporting and facilitating clinical and translational "team science". The UM CTSA will be housed in the newly created Michigan Institute of Clinical and Health Research (MICHR). MICHR was created by the University to maximize the potential of an institution that is extremely supportive of interdisciplinary research and has tremendous strengths in the health sciences. MICHR creates a partnership between relevant unit of the University, the NIH, external industry partners, and the community. The overwhelming majority of UM schools, colleges, and institutes are participating, including the top-ranked Schools of Business, Dentistry, Medicine, Nursing, Social Work, and Public Health, the Colleges of Engineering, Pharmacy, and Literature, Science and Arts, the Division of Kinesiology, the Institute of Social Research, and the Life Sciences Institute. The University-owned Health System, which includes integrated outpatient and inpatient facilities, is contributing significantly to a strong partnership with the UM CTSA. The Director of MICHR is the PI of the UM CTSA grant, and reports to a University Executive Vice President, who also oversees the Medical School and Health System. In addition to the grant resources, the institution is contributing nearly $11 million/vr of in-kind support, cost-sharing, support of pilot and recruitment programs, and renovation costs, a more than 11 match of NIH dollars. Blue Cross Blue Shield of Michigan and Pfizer are also making sizable investments. Departments are also contributing more than 100 FTE in potential faculty effort, so that MICHR can grant effort for pilot studies, K- 12, and new "mini-K programs". These aggregate resources are used to create robust infrastructure and support based on strong existing units and programs, as well as academic programs in key clinical and translational disciplines, to provide faculty leadership, expertise, and consultation as well as high quality services. These Programs are in Biomedical Informatics, Biostatistics, Clinical Translation, Novel Methods, Technical Cores, Community Engagement, Ethics, Health Disparities, Pediatrics, and Regulatory Support. A radically reconfigured Participant and Clinical Interactions Resource is also described. These programs are all united by an Education Program that reaches a wide spectrum of audiences from undergraduates to mid-career faculty, from basic scientists to population researchers, from staff to community members. Both accelerated options and intensive programs are available. Finally, a robust pilot program will disburse up to $8 million/yr in pilot funds, focusing on stimulating translationaland interdisciplinary studies
Keywords: Arts; Award; base; Biological Sciences; biomedical informatics; Biometry; Blue Cross; Blue Shield; Businesses; career; Clinical; Clinical and Translational Science Awards; Clinical Sciences; college; Communities; Consultations; cost; Cost Sharing; Dentistry; Discipline; Discipline of Nursing; Educational aspects; Engineering; Ethics; Faculty; Funding; Grant; Health; health disparity; Health Sciences; Health system; Housing; industry partner; Inpatients; Institutes; Institution; Interdisciplinary Study; Investments; Kinesiology; Leadership; Literature; medical schools; Medicine; member; Methods; Michigan; novel; Outpatients; Participant; Pediatrics; Pharmacy facility; Pilot Projects; Population; programs; public health medicine (field); Reporting; Research; Research Infrastructure; Research Personnel; Resources; Schools; Science; Scientist; Services; social; Social work (field); Translational Research; Translations; United States National Institutes of Health; Universities
Project start date: 2007-09-17
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-RM-07-002
5UL1RR024986-05 (2011): $9902460
3UL1RR024986-05S1 (2011): $497901
3UL1RR024986-05S2 (2011): $410696
3UL1RR024986-05S3 (2011): $418257
ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION AND THE INITIATION OF OSTEOARTHRITIS
P Thomas, Professor
Stanford Universitycity: Stanford country: United States (us)
Grant 5R01AR039421-15 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: The overall goal of this project is to address the problem of premature osteoarthritis of the knee in patients following anterior cruciate ligament (ACL) injury by conducting a prospective study to fill critical gaps in the available knowledge on the nature of walking mechanics changes, graft function and cartilage thinning following ACL reconstruction. This work is important since ACL loss often leads to premature degenerative arthritis of the knee even when the ACL is reconstructed and there is increasing evidence that there are kinematic and kinetic changes at the knee during walking following ACL injury or reconstruction that influence cartilage changes over time. Preliminary work for this project has demonstrated that changes in tibiofemoral motion of the ACL deficient knee during walking were associated with cartilage thinning in the tibiofemoral joint and a significant relationship between graft placement and ambulatory mechanics was observed following ACL reconstruction. Patients operated within 3 months following ACL injury will be studied at 2 years following reconstruction (to ensure remodeling is stable) and at 4 years after surgery. A matched control population will also be studied over the same interval. The study will address the following specific aims 1) To determine if ambulatory kinematics in patients with ACL reconstruction are influenced by graft placement. 2.) To determine if there are detectable thickness changes in the weight bearing regions of tibiofemoral cartilage over a 2 year period following ACL reconstruction that are greater than a matched healthy control group 3) To determine if specific characteristics of walking mechanics of the ACL reconstructed knees remain unchanged, or change no more than matched healthy knees, between 2 and 4 years after reconstruction for clinically successful grafts. This study will use a combination of in vivo gait analysis and 3.0T magnetic resonance imaging. Using algorithms developed by our group, we can estimate the 6 degree-of-freedom motion of the tibiofemoral joint including internal tibial rotation and anterior tibial translation. Custom algorithms also allow for the high- resolution measurement of cartilage thickness across weight-bearing regions of the cartilage. This project is important clinically since the information generated from this study will helps to isolate the some critical factors that can influence premature osteoarthritis following ACL reconstruction and thus can be used to inform improved methods for treatment planning, reconstruction and rehabilitation. The overall goal of this project is to address the problem of premature osteoarthritis of the knee in patients following anterior cruciate ligament (ACL) injury and treated with an ACL reconstruction using a graft. This study will fill critical gaps in the available knowledge on the nature of walking mechanics changes, graft function and cartilage thinning following ACL reconstruction. This work is important since ACL loss often leads to premature degenerative arthritis of the knee even when the ACL is reconstructed and there is increasing evidence that there are kinematic and kinetic changes at the knee during walking following ACL injury or reconstruction that influence cartilage changes over time
Keywords: Acute; Address; Age; Algorithms; Anterior; Anterior Cruciate Ligament; anterior cruciate ligament reconstruction; articular cartilage; Articular Range of Motion; Cartilage; Characteristics; Clinical; Control Groups; Custom; Data; Degenerative polyarthritis; Ensure; Femur; Freedom; gait examination; Gender; Goals; graft function; Health; Height; Human; improved; in vivo; Joints; kinematics; Kinetics; Knee; Knee Osteoarthritis; Knowledge; Lesion; ligament injury; Magnetic Resonance Imaging; Maps; Measurement; Mechanics; meetings; Meniscus structure of joint; Methods; Morphology; Motion; Nature; Operative Surgical Procedures; patient population; Patients; Phase; Population; Population Control; Population Study; premature; Prospective Studies; reconstruction; Rehabilitation therapy; Resolution; Rotation; Sports Medicine; Testing; Thick; tibia; Time; Translations; treatment planning; Variant; Walking; Weight; Weight-Bearing state; Work
Relevance: The overall goal of this project is to address the problem of premature osteoarthritis of the knee in patients following anterior cruciate ligament (ACL) injury and treated with an ACL reconstruction using a graft. This study will fill critical gaps in the available knowledge on the nature of walking mechanics changes, graft function and cartilage thinning following ACL reconstruction. This work is important since ACL loss often leads to premature degenerative arthritis of the knee even when the ACL is reconstructed and there is increasing evidence that there are kinematic and kinetic changes at the knee during walking following ACL injury or reconstruction that influence cartilage changes over time
Project start date: 1988-04-01
Project end date: 2013-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01AR039421-15 (2011): $342144
DEVELOPMENT OF ROR LIGANDS FOR TREATMENT OF CIRCADIAN RHYTHM DISORDERS
P Thomas, Professor
Scripps Research Institutecity: La Jolla country: United States (us)
Grant 1R01MH092769-01 from National Institute Of Mental Health
Abstract: The nuclear hormone receptor superfamily (NHR) and ligand regulated transcription factors that have proven to be a rich source of targets for development of drugs that target myriad human diseases. The retinoic acid receptor-related orphan receptors (RORs) are members of this superfamily and regulate several physiological processes including the circadian rhythm, metabolism and the immune response. We recently identified the first selective synthetic ligands that target ROR, a critical regulator of the circadian rhythm. Our long-term goal is to develop ligands targeting RORs that can be used to treat diseases associated with dysregulation of the circadian rhythm such as bipolar and sleep disorders as well as schizophrenia. The initial lead compound (T0901317) has less than optimal properties for use as a drug targeting ROR and our preliminary data indicates that we can significantly improve its drug like properties. We hypothesize that optimized ROR ligands, based on the T0901317 chemical scaffold, with improved pharmacodynamic, pharmacokinetic, and receptor selectivity properties will have efficacy in modulation of the circadian rhythm. In order to address this hypothesis we will focus on the following specific aims 1) Develop and optimize ROR ligands with improved pharmacokinetic and pharmacodynamic properties targeting the central nervous system; 2) Characterize the actions of ROR ligands on the circadian rhythm in animals. We predict that this research will provide novel, innovative ligands that modulate ROR1 activity that will have potential utility to treat sleep disorders as well as other disorders associated with dysregulation of the circadian rhythm including biopolar disorder and schizophrenia. The nuclear hormone receptor superfamily (NHR) has proven to be a rich source of targets for development of drugs that target myriad human diseases and we recently identified the first selective synthetic ligands for the retinoic acid receptor-related orphan receptors (RORs). This receptor is a key regulator of the circadian rhythm and dysregulation of the circadian rhythm is associated with several disorders of the nervous system including bipolar and sleep disorders. The goal of this proposal is to develop ROR ligands with optimized pharmacodynamic and pharmacokinetic properties and appropriate receptor selectivity profiles that we will evaluate for their ability to modulate circadian function in vivo
Keywords: Address; Affective Psychosis, Bipolar; Animals; Assay; base; Bioassay; Biologic Assays; Biological Assay; bipolar affective disorder; Bipolar Disorder; Central Nervous System; chemical structure function; Chemicals; circadian; Circadian Dysregulation; circadian process; Circadian Rhythm Disorder; Circadian Rhythms; daily biorhythm; Data; dementia praecox; Depression; design; designing; Development; Disease; disease/disorder; Disorder; Diurnal Rhythm; diurnal variation; Drug Delivery; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug Targetings; drug/agent; Drugs; Goals; Health; heavy metal lead; heavy metal Pb; host response; Human; human disease; Human, General; Immune response; immunoresponse; improved; in vivo; innovate; innovation; innovative; Intermediary Metabolism; Lead; Ligands; Mammals, Mice; Man (Taxonomy); Man, Modern; manic depressive disorder; manic depressive illness; Medication; member; Mental Depression; Metabolic Processes; Metabolism; METBL; Mice; mRNA Expression; Murine; Mus; Nervous System Diseases; nervous system disorder; Nervous System, CNS; Neuraxis; Neurologic Disorders; neurological disease; Neurological Disorders; novel; NR1F1; Nuclear Hormone Receptor Superfamily; Nuclear Hormone Receptors; Nyctohemeral Rhythm; Organism-Level Process; Organismal Process; Orphan; Pathologic Processes; Pathological Processes; Pathology; pathway; Pathway interactions; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Pharmacology; Physiologic; Physiologic Processes; Physiological; Physiological Processes; Property; Property, LOINC Axis 2; Psychoses; Psychosis, Manic-Depressive; Psychotic Disorders; public health relevance; receptor; Receptor Protein; Regulation; Research; Retinoic Acid Receptor; Role; ROR1; ROR2; ROR3; RORA; RORA gene; RZRA; scaffold; scaffolding; Scheme; Schizophrenia; schizophrenic; Schizophrenic Disorders; Sleep Disorders; sleep problem; social role; Source; structure function relationship; Structure-Activity Relationship; Synthesis Chemistry; Synthetic Chemistry; Testing; tool; transcription factor; Twenty-Four Hour Rhythm
Relevance: NARRATIVE The nuclear hormone receptor superfamily (NHR) has proven to be a rich source of targets for development of drugs that target myriad human diseases and we recently identified the first selective synthetic ligands for the retinoic acid receptor-related orphan receptors (RORs). This receptor is a key regulator of the circadian rhythm and dysregulation of the circadian rhythm is associated with several disorders of the nervous system including bipolar and sleep disorders. The goal of this proposal is to develop ROR ligands with optimized pharmacodynamic and pharmacokinetic properties and appropriate receptor selectivity profiles that we will evaluate for their ability to modulate circadian function in vivo
Project start date: 2010-12-22
Project end date: 2014-11-30
Budget start date: 22-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PAR-10-001
1R01MH092769-01 (2011): $814847
PROTOCADHERIN GENE EXPRESSION AND FUNCTION
P Thomas
Columbia University Health Sciencescity: New York country: United States (us)
Grant 5R01NS043915-32 from National Institute Of Neurological Disorders And Stroke
Abstract: The long term objective of the proposed research is to advance the understanding of how specific neuronal connections are established and maintained in the mammalian brain. This objective will be approached by studying the regulation and function of the clustered protocadherin (Pcdh) genes, which encode a family of cell surface proteins that localize to synaptic junctions. The unique organization of the Pcdh gene clusters, combined with cell-specific promoter activation and alternative pre-mRNA splicing, provides the potential for generating enormous protein diversity at the cell surface. This diversity could function as a molecular code for synaptic specificity. The regulation of Pcdh gene expression will be approached in two ways. First, regulatory proteins that bind to Pcdh promoters and intergenic regulatory DNA sequences will be identified and their functions determined through both in vivo and in vitro studies. The exciting possibility that these factors function in the coupling of transcription and splicing will be tested. Second, extra copies of well characterized Pcdh intergenic regulatory DNA sequences will be inserted into the Pcdh gene cluster to determine whether the limited number of Pcdh isoforms expressed from each chromosoome is a consequence of enhancer/promoter competition. Two approaches will be taken to determine the function of Pcdh proteins. First, Pcdh signaling pathways will be studied by identifying and characterizing the function of proteins that interact with Pcdhs in vivo and by identifying the genes they regulate. Second, mice bearing targeted mutations in the Pcdh gene clusters will be systematically characterized using histological and electrophysiological methods and behavioral paradigms. These studies should provide important new insights into the regulatory mechanisms for generating protein diversity in the brain, the function of Pcdh genes, and the pathological consequences of their loss of function. Interactions between neurons underlie normal brain function, and aberrant connectivity can lead to neurological and psychiatric disorders. A critical feature of brain function is the specificity of neuronal wiring. A better understanding of the mechanisms involved in this wiring may lead to a better understanding and treatment of mental illnesses, such as autism, schizophrenia and bipolar disease
Keywords: Affinity Chromatography; affinity purification; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Be element; Be++ element; Behavioral Paradigm; Beryllium; biological signal transduction; Brain; Cadherins; Cell Communication and Signaling; Cell Signaling; Cell surface; Cell Surface Proteins; Cells; Chromatography, Affinity; Code; Coding System; Conserved Sequence; Coupling; dementia praecox; Disease; disease/disorder; Disorder; DNA Sequence; Encephalon; Encephalons; Enhancers; Exons; Family; Gene Action Regulation; Gene Cluster; Gene Expression; Gene Expression Regulation; gene function; gene product; Gene Regulation; Gene Regulation Process; Gene Targeting; Gene Transcription; Genes; Genetic Alteration; Genetic Change; Genetic defect; genetic regulatory protein; Genetic Transcription; genome mutation; heavy metal lead; heavy metal Pb; In Vitro; in vivo; Individual; insight; Integral Membrane Protein; Intracellular Communication and Signaling; Intrinsic Membrane Protein; Isoforms; Kanner`s Syndrome; Lead; liver cell adhesion molecule; Liver Cell Adhesion Molecules; loss of function; Mammals, Mice; Mental disorders; Mental health disorders; mental illness; Methods; Mice; Mice, Mutant Strains; Molecular; mouse mutant; mRNA Precursor; Murine; Mus; Mutant Strains Mice; Mutation; Nerve Cells; Nerve Unit; Nervous System; Nervous System Diseases; nervous system disorder; Nervous system structure; Nervous System, Brain; Neural Cell; Neurocyte; Neurologic Body System; Neurologic Disorders; Neurologic Organ System; neurological disease; Neurological Disorders; neuronal; Neurons; NRVS-SYS; Pb element; Physiologic; Physiological; Pre-mRNA; premRNA; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Protein Binding; protein function; Protein Isoforms; Proteins; Psychiatric Disease; Psychiatric Disorder; psychological disorder; Regulation; Regulatory Element; regulatory gene product; Regulatory Protein; RegulatoryElement; Relative; Relative (related person); Research; RNA Expression; RNA Splicing; RNA, Messenger, Precursors; Role; Schizophrenia; schizophrenic; Schizophrenic Disorders; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; social role; Specificity; Splicing; Synapses; Synaptic; Targetings, Gene; Testing; Transcription; Transcription, Genetic; Transmembrane Protein; Unspecified Mental Disorder
Project start date: 1981-04-01
Project end date: 2012-02-29
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5R01NS043915-32 (2011): $606881
NEURO-IMMUNOPHYLLIN LIGAND MECHANISM OF ACTION IN REDUCING ALCOHOL PREFERENCE
P Thomas
Denver Research Institutecity: Denver country: United States (us)
Grant 5R21AA016294-02 from National Institute On Alcohol Abuse And Alcoholism
Abstract: The long term goal of this proposed study is to ask whether non-immunosuppressant congeners of the neuro-immunophyllin ligands may be useful in the treatment of alcohol dependence (AD). A widespread and clinically important problem, AD affects 7-10% of the U.S. population and carries an estimated economic burden of more than $160 billion annually. Medication choices for the treatment of AD today are few due to low efficacy of currently approved agents. Neuro-immunophyllin ligands, such as cyclosporine-A (CsA), have been used in preventing tissue rejection in solid organ transplantation for the past twenty years, including liver transplants provided for AD patients, an area of the Principal Investigator´s expertise. Until recently, no connection was made between neuro-immunophyllin ligand exposure and concurrently high, and sustained, rates of abstinence from alcohol among AD liver transplant recipients reported across centers rates as high as 70-75% after three years. We hypothesized that neuro-immunophyllin ligand exposure might contribute to this effect. To test this in controlled pilot study, we gave CsA to alcohol drinking C57b1/6j mice. CsA significantly (p<0.0000) and persistently reduced alcohol preference in the treated mice. (Beresford, HF, Deitrich, RA, Beresford. TP. Cyclosporine-A Discourages Ethanol Intake In C57b1/6j Mice a Preliminary Study. Journal of Studies on Alcohol, September, 2005). It is not known, however, whether the significant and sustained reduction in preference that we observed depends on calcineurin inhibition or immunophyllin inhibition in the brain, two of the principal known mechanisms of action of this class of pharmacologic agents. Therefore, the proposed investigation will address the alcohol preference effects of a series of immunosuppressant agents, as well as one non-suppressive variant of the CsA molecule. We hypothesize that only agents interacting with specific immunophyllin receptors will demonstrate this effect. This will be tested in rodent experiments designed to assess 1) whether calcineurin inhibition or 2) immunophyllin inhibition may be possible mechanism(s) of action for those agents that alter alcohol preference. In preparation for eventual human application, we will characterize the kinetic and toxicity profiles of the study agents in rodents. We anticipate that our results will lead to a clinical application of neuro-immunophyllin ligands free of immuno-suppressive properties that may be effective treatment(s) for AD in humans. The future direction of this study will include clinical testing of related non-immunosuppressant agents that basic investigations deem successful
Keywords: 21+ years old; Abbreviations; abstaining from alcohol; abstaining from ethanol; Abstinence; abstinence from alcohol; abstinence from ethanol; acamprosate; acamprostate; Address; Adult; adult human (21+); Adverse effects; Affect; alcohol abstinence; Alcohol abuse; alcohol addiction; alcohol addiction therapy; Alcohol consumption; Alcohol dependence; alcohol dependence therapy; alcohol dependency; Alcohol Drinking; alcohol ingestion; alcohol intake; alcohol problem; alcohol product use; alcohol use; alcohol-dependent; alcoholic beverage consumption; Alcoholic Beverages; alcoholic drink intake; alcoholism therapy; Alcohols; alpha-D-Glucopyranoside, beta-D-fructofuranosyl; American; analog; Animal Model; Animal Models and Related Studies; Animal Testing; Animals; Antabuse; Antidepressant Agent; Antidepressant Drugs; Antidepressants; Antidepressive Agents; AOTA; Appetite; Area; Biological; biological signal transduction; Bis(diethylthiocarbamoyl) Disulfide; Blood; Body Tissues; Brain; Bristol-Myers Squibb Brand of Naltrexone Hydrochloride; Calcineurin; Calcineurin antagonist; Calcineurin inhibitor; Caring; Cell Communication and Signaling; Cell Signaling; Chemical Class, Alcohol; Ciclosporin; Clinical; clinical applicability; clinical application; Clinical Evaluation; clinical test; Clinical Testing; Clinical, Transplantation, Organ; Consumption; consumption measures; Control Animal; CsA; Cyclosporin A; Cyclosporine; Cyclosporine A; design; designing; Desire for food; Development; Disease; disease/disorder; Disorder; Disulfiram; Dose; drinking; Drug Kinetics; drug/agent; Drugs; Du Pont Brand of Naltrexone Hydrochloride; Economic Burden; Economics; effective therapy; Effectiveness; Encephalon; Encephalons; ethanol abstinence; ethanol abuse; ethanol addiction; ethanol consumption; Ethanol dependence; ethanol dependency; ethanol drinking; ethanol ingestion; ethanol intake; ethanol product use; ethanol use; ethanol-dependent; EtOH drinking; etoh use; Exhibits; experiment; experimental research; experimental study; FK 506; FK506; Future; Goals; Grafting Procedure; Grafting, Liver; hazardous alcohol use; Healed; healing; Health; heavy metal lead; heavy metal Pb; Human; human subject; Human, Adult; Human, General; Immunosuppressants; immunosuppression; Immunosuppression Effect; Immunosuppressions (Physiology); immunosuppressive; Immunosuppressive Agents; Immunosuppressive Effect; in vivo; Intracellular Communication and Signaling; Investigation; Journals; Kinetic; Kinetics; Lamepro Brand of Naltrexone Hydrochloride; Lead; Ligands; Link; Liver Transplant; liver transplantation; Magazine; Mammals, Mice; Mammals, Rodents; Man (Taxonomy); Man, Modern; Measures; Medical; Medical center; Medication; Metabolic; Methods; Mice; MMF; model organism; Modeling; Molecular; Molecular Target; Monitor; Morphinan-6-one, 17-(cyclopropylmethyl)-4, 5-epoxy-3, 14-dihydroxy-, (5alpha)-; Murine; Mus; mycophenolate mofetil; Mycophenolate Mofetil (Cellcept); mycophenolic acid morpholinoethyl ester; N-acetylhomotaurine; Nalorex; Naltrexone; Natural immunosuppression; Nature; Nemexin; neoral; Nervous System, Brain; organ allograft; organ graft; Organ Transplantation; Organ Transplants; Organ Transplants, Including Bone Marrow for DCT; organ xenograft; Orphan Brand of Naltrexone Hydrochloride; Patients; Pb element; Persons; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Pilot Projects; pilot study; Population; Postoperative Care; PP2B; preference; Preparation; prevent; preventing; Principal Investigator; problem drinking; Process; Productivity; Property; Property, LOINC Axis 2; Protein Phosphatase-2B; psychologic; psychological; receptor; Receptor Protein; Reporting; Research; research clinical testing; research study; Reticuloendothelial System, Blood; ReVia; Rewards; Rodent; Rodentia; Rodentias; Saccharose; Sandimmun; sandimmune; SangCya; Schering-Plough Brand of Naltrexone Hydrochloride; Selective serotonin re-uptake inhibitor; Selective Serotonin Reuptake Inhibitor; Self Administration; Series; serotonin reuptake inhibitor; side effect; Signal Transduction; Signal Transduction Systems; Signaling; social; Solid; Solutions; SSRI; success; Sucrose; Testing; Tetraethylthioperoxydicarbonic Diamide, ((H2N)C(S))2S2; Tetraethylthiuram Disulfide; therapy adverse effect; Thioperoxydicarbonic diamide (((H2N)C(S))2S2), tetraethyl-; Tissues; Toxic effect; Toxicities; transplant; transplant patient; Transplant Recipients; Transplantation; Transplantation of liver; Transplantation Surgery; Transplantation, Hepatic; treatment adverse effect; Treatment Side Effects; United Drug Brand of Naltrexone Hydrochloride; Variant; Variation
Project start date: 2008-09-30
Project end date: 2011-08-31
Budget start date: 1-SEP-2009
Budget end date: 31-AUG-2011
PFA/PA: PA-06-181
5R21AA016294-02 (2009): $152950
REGULATION OF TOR SIGNALING AND AUTOPHAGY IN DROSOPHILA
P Thomas, Associate Professor
University Of Minnesota Twin Citiescity: Minneapolis country: United States (us)
Grant 5R01GM062509-11 from National Institute Of General Medical Sciences
Abstract: The long term goal of this project is to understand the regulation and physiological roles of autophagy, a process by which proteins, organelles and bulk cytoplasm are sequestered within autophagic vesicles and delivered to the lysosome for degradation. This process plays several distinct, vital roles in the cell, acting to recycle aged or damaged components, to provide a source of nutrients in response to starvation, and in some cases to initiate cell death. These cellular functions underlie the impact of autophagy on a broad range of human illnesses. Fundamental questions regarding autophagy remain to be addressed, including how autophagy is regulated by nutrients and other signals, how substrates are selectively targeted for degradation, and how autophagy can promote either cell survival or cell death in different contexts. The proposed studies will use genetic, biochemical and imaging-based approaches in the Drosophila system to help define mechanisms of autophagy regulation and its functions in an intact organism. Recent studies in Drosophila and mammalian cells have delineated key factors in a conserved signaling pathway that inhibits autophagy under favorable nutrient conditions. The central component of this nutrient-sensing pathway, the Ser/Thr protein kinase Target of Rapamycin (TOR), was shown to control the activity of a multicomponent complex containing the autophagy related kinase Atg1 and the phosphoprotein Atg13. Specific aims of this project are to 1) test potential models of Atg1/13 complex regulation, including the effects of phosphorylation, multimerization, and association with novel inhibitory cofactors. Potential roles of PKA in this regulation as well as the function of the Atg1-related kinase Ulk3 will be characterized. 2) investigate mechanisms and consequences of a novel self-reinforcing feedback signal by which Atg1 inhibits TOR signaling. 3) investigate mechanisms by which Atg1 overexpression leads to autophagy-dependent cell death. As preliminary indicate of a role for Jun kinase (Jnk) signaling, the mechanisms of autophagy induction by Jnk and the roles of autophagy in endogenous Jnk-mediated death will be explored. 4) identify and characterize the functions of novel autophagy regulators and substrates through genetic and proteomic screens. Experiments in these aims were selected for their likelihood of having a high impact on key questions important to the field of autophagy. This proposal makes use of recently developed reagents including knockouts of several autophagy-related (Atg) genes, in vivo markers of autophagic activity, and novel methods of genetic manipulation. Information gained from studies of autophagy in Drosophila will provide an important whole- animal complement to mammalian cell culture-based studies. Defects in autophagy lead to adverse effects on several areas of human health, including cancer, neurodegeneration, inflammatory disease, myopathies, and ischemic injury. Potential therapeutic approaches that involve inhibiting or potentiating autophagy will benefit from greater understanding of how regulators and effectors of autophagy interact to control this process
Keywords: 1-Phosphatidylinositol 3-Kinase; Address; Adverse effects; aged; Aging; Animals; Antithymoglobulin; Apoptosis; Area; Autophagocytosis; Awareness; base; Biochemical; caspase; Cell Culture Techniques; Cell Death; Cell Death Signaling Process; cell growth; Cell physiology; Cell Survival; Cells; Cessation of life; cofactor; Complement; Complex; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Defect; detection of nutrient; Development; Dimerization; Disease; Drosophila genus; Environment; Eukaryotic Cell; Event; Feedback; fly; gene discovery; Genes; Genetic; genetic manipulation; Genetic Screening; Goals; Grant; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Health; Human; Image; in vivo; Infection; Inflammatory; Injury; interest; Ischemia; Knock-out; Lead; Life; Link; Lysosomes; Malignant Neoplasms; Mammalian Cell; Mediating; Mediator of activation protein; Methods; Modeling; Multiprotein Complexes; Mutation; Myopathy; Nerve Degeneration; novel; Nutrient; nutrition; Organelles; Organism; overexpression; Pathway interactions; Phosphoproteins; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Play; Process; Protein Kinase; Proteins; Proteomics; public health relevance; Reagent; Recycling; Regulation; research study; response; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Sirolimus; Source; Starvation; stem; Stress; System; Testing; Therapeutic; trafficking; Vesicle; Work; Yeasts
Relevance: Public Health Relevance Defects in autophagy lead to averse effects on several areas of human health, including cancer, neurodegeneration, inflammatory disease, myopathies, and ischemic injury. Potential therapeutic approaches that involve inhibiting or potentiating autophagy will benefit from greater understanding of how regulators and effectors of autophagy interact to control this process
Project start date: 2001-03-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01GM062509-11 (2011): $371958
Sponsored Links Excellgen http://Excellgen.com
DEVELOPMENT AND VALIDATION OF A REV-ERBALPHA HTS ASSAY
P Thomas, Professor
Scripps Research Institutecity: La Jolla country: United States (us)
Grant 1R21NS066417-01 from Roadmap Initiative, Office Of The Director
Abstract: The human nuclear hormone receptor (NHR) super family consists of 48 members, approximately half of which have no identified ligands and are termed "orphan receptors". Nearly all of the NHRs with identified ligands have been successful targets for drugs treating a variety of diseases including diabetes, dyslipidemia, inflammation, and cancer. REV-ERB1 and REV-ERB1 were originally identified as orphan members of the NHR super family and play critical roles in control of lipid and glucose metabolism and the circadian rhythm. We recently discovered that REV-ERBs are indeed ligand-regulated and that the porphyrin, heme, behaves as an agonist binding directly to the receptors and altering their transcriptional activities. Beyond the natural ligand, heme, there are no validated synthetic ligands to use as probes to characterize the biological roles of the REV- ERBs. The aim of this project is to develop an HTS amenable assay and appropriate secondary assays to identify and characterize REV-ERBa ligands. Identification of REV-ERB ligands is essential to address the physiological function of these receptors. Additionally, due to the critical role that the REV-ERBs play in regulation of lipid and glucose metabolism, REV-ERBa ligands may be used as drugs that target disorders associated with dysregualtion of metabolic pathways including type 2 diabetes and cardiovascular disease. REV-ERB1 is a nuclear hormone receptor that plays critical role in control of lipid and glucose metabolism and the circadian rhythm. The aim of this project is to develop assays to be used to identify REV-ERB1 ligands in a high throughput screen. Identification of REV-ERB1 ligands is essential to examine the physiological function of this receptor as well as to develop drugs that could be used to treat disorders such as type 2 diabetes and cardiovascular disease
Keywords: Address; adult onset diabetes; Agonist; Assay; Binding; Binding (Molecular Function); Bioassay; Biochemical; Biologic Assays; Biological; Biological Assay; Cancers; Cardiovascular Diseases; cardiovascular disorder; circadian; circadian process; Circadian Rhythms; daily biorhythm; Development; diabetes; Diabetes Mellitus; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Ketosis-Resistant; Diabetes Mellitus, Non-Insulin-Dependent; Diabetes Mellitus, Noninsulin Dependent; Diabetes Mellitus, Slow-Onset; Diabetes Mellitus, Stable; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type II; Disease; disease/disorder; Disorder; Diurnal Rhythm; diurnal variation; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; drug/agent; Drugs; Dyslipidemias; Family; Ferrate(2-), (7, 12-diethenyl-3, 8, 13, 17-tetramethyl-21H, 23H-porphine-2, 18-dipropanoato(4-)-N21, N22, N23, N24)-, dihydrogen, (SP-4-2)-; ferroheme; Ferroprotoporphyrin; glucose metabolism; Heme; Heme b; High Throughput Assay; high throughput screening; Human; Human, General; Inflammation; INFLM; innovate; innovation; innovative; ketosis resistant diabetes; Ligands; Lipids; malignancy; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; maturity onset diabetes; Maturity-Onset Diabetes Mellitus; Medication; member; Metabolic Pathway; MODY; Molecular Interaction; neoplasm/cancer; NIDDM; Non-Insulin Dependent Diabetes; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptor Superfamily; Nuclear Hormone Receptors; Nyctohemeral Rhythm; Orphan; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiologic; Physiological; Play; Porphyrins; Protoheme; Protoheme IX; public health relevance; receptor; receptor function; Receptor Protein; Regulation; Role; Scheme; screening; Screening procedure; screenings; small molecule libraries; social role; T2D; T2DM; Transcription Corepressor; Transcription Repressor; Transcription Repressor/Corepressor; Transcriptional Corepressor; Transcriptional Repressor; Transcriptional Repressor/Corepressor; Twenty-Four Hour Rhythm; Type 2 diabetes; Type II diabetes; Validation
Relevance: REV-ERB¿ is a nuclear hormone receptor that plays critical role in control of lipid and glucose metabolism and the circadian rhythm. The aim of this project is to develop assays to be used to identify REV-ERB¿ ligands in a high throughput screen. Identification of REV-ERB¿ ligands is essential to examine the physiological function of this receptor as well as to develop drugs that could be used to treat disorders such as type 2 diabetes and cardiovascular disease
Project start date: 2009-06-05
Project end date: 2011-05-31
Budget start date: 5-JUN-2009
Budget end date: 31-MAY-2011
PFA/PA: PAR-08-024
1R21NS066417-01 (2009): $194500
TEST OF AN INTERVENTION TO IMPROVE RETENTION IN HIV CARE AFTER HOSPITALIZATION
P Thomas, Assistant Professor
Baylor College Of Medicinecity: Houston country: United States (us)
Grant 5R01MH085527-03 from National Institute Of Mental Health
Abstract: Poor retention in medical care is one of the primary reasons people die of HIV/AIDS today. Modern HIV treatment has transformed this deadly infection into a treatable chronic condition. There are no proven interventions to better retain people in HIV primary care. Hospitalized patients with HIV infection are at high risk for poor retention in care. A single or dual session intervention is essential for most patients out of care, because any patient who could be recruited into a multi-session intervention could likely be recruited back into primary care. Our team has been researching retention in HIV care for over 7 years. Using the information-motivation-behavioral skills model as a framework, our data indicate that among patients recently diagnosed with HIV infection, access to HIV primary care is affected by critical information gaps regarding the availability of care and treatment, limited motivation related to poor coping strategies and low trust in the healthcare system, and weak behavior skills reflected in low self-efficacy and social support around adherence to HIV care. These factors result in poor ability to navigate the health care system and remain in HIV care. We have developed a structured, theory-based, Patient Mentor Program. The Patient Mentor Program was developed to improve retention into HIV primary care by increasing patient knowledge about HIV and the care system, increasing self-efficacy, and promoting active self-management. In a one- time interaction at the Thomas Street Health Center, volunteer patient mentors greet new patients who are arriving for their intake visit to the clinic, guide them through the intake visit and support them. In our preliminary, quasi-experimental data, 88% of patients who had a patient mentor during that intake visit completed a physician visit within the next 90 days, compared to 78% of patients who did not have a mentor (p<.001). These effects remained significant after adjusting for baseline demographic and clinical characteristics, and persisted into the 90-180 day interval after intake. We will test the efficacy of the TSHC patient mentor intervention in a 5-year randomized, controlled trial in 434 socio-economically and racially diverse HIV-infected patients hospitalized at Ben Taub General Hospital. We hypothesize that the intervention will meaningfully increase retention in HIV primary care after discharge compared to an attention control. Our Specific Aims are 1) To test the efficacy of the patient mentor intervention on retention in HIV primary care after hospital discharge; 2) To test the efficacy of a patient mentor intervention on secondary outcomes that include health services use, health-related quality of life, and clinical outcomes; 3) To determine the mediating factors associated with response to the intervention, and the individual and system facilitators and barriers to retention in HIV primary care. This study addresses one of the most important challenges in HIV care today, i.e., expanding modern HIV treatment to all those in need, and may also impact race-based disparities in the health of people with HIV infection. Poor retention in medical care is one of the primary reason people die of HIV/AIDS today. We have developed a structured, theory-based, Patient Mentor Program to improve retention into HIV primary care. We will test the efficacy of this patient mentor intervention in a 5-year randomized, controlled trial in more than 400 socio-economically and racially diverse HIV-infected patients hospitalized at Ben Taub General Hospital
Keywords: Accident and Emergency department; Acquired Immunodeficiency Syndrome; Address; Adherence (attribute); Affect; Aftercare; AIDS/HIV problem; Attention; Back; base; Behavior; Behavioral; care systems; Caring; CD4 Lymphocyte Count; Characteristics; Chronic; Clinic; Clinical; Complex; coping; cost effective; Country; Data; Developed Countries; Diagnosis; Educational process of instructing; efficacy testing; General Hospitals; Goals; Health; Health care facility; health related quality of life; Health Services; Healthcare Systems; high risk; Highly Active Antiretroviral Therapy; HIV; HIV Infections; Hospital Readmission; Hospitalization; Hospitals; improved; Individual; Infection; Intake; Intervention; Intervention Trial; Knowledge; knowledge base; Length of Stay; Life; Low income; Mediating; Medical; Mentors; Modeling; Morbidity - disease rate; Mortality Vital Statistics; Motivation; Outcome; Outpatients; Patient Care; patient oriented; Patients; Pattern; Physicians; Population Heterogeneity; prevent; Primary Health Care; primary outcome; programs; Public Hospitals; Race; racial and ethnic disparities; Randomized Controlled Trials; Recruitment Activity; Research; response; secondary outcome; Self Efficacy; Self Management; skills; Social support; Structure; successful intervention; System; Testing; theories; Time; Trust; Viral Load result; Visit; volunteer
Relevance: Poor retention in medical care is one of the primary reason people die of HIV/AIDS today. We have developed a structured, theory-based, Patient Mentor Program to improve retention into HIV primary care. We will test the efficacy of this patient mentor intervention in a 5-year randomized, controlled trial in more than 400 socio-economically and racially diverse HIV-infected patients hospitalized at Ben Taub General Hospital
Project start date: 2009-09-30
Project end date: 2014-05-31
Budget start date: 1-AUG-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-338
5R01MH085527-03 (2011): $704865
VISUALIZING ACTOMYOSIN TRANSIENTS BY DATA MERGING
P Thomas, Consultant
Mayo Cliniccity: Rochester country: United States (us)
Grant 5R01AR049277-08 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: Myosin is a molecular motor binding ATP and actin to produce work by causing relative translation of the two proteins. Myosin contains a lever arm probably executing a power stroke by rotating through an angle of ~70o to translate actin against resistive force. ATP hydrolysis at myosin´s active site energizes contraction by influencing lever arm movement and is influenced by allostery with actin in actin-activation of myosin ATPase. The influences are conducted through the protein matrix by coupling pathways investigated by mutation (naturally occurring and computation inspired), molecular dynamics simulation (MD), and structure/function assays. Two coupling pathways identified for study mediate actin-activation of myosin ATPase and conformation change triggering tryptophan nucleotide sensitivity that might link small active site displacements to the larger lever arm movement. The goal of the project is to elucidate the native relationships among actin binding, active site conformation, lever arm rotation and protein displacement and then to observe how these relationships are affected by modifications introduced to coupling pathways. Human skeletal myosin variants play a fundamental role in exercise physiology, human disease, and population diversity. The variants involve widely dispersed amino acid substitutions covering several regions essential to function and are naturally embedded clues to discovering functional domain interconnectedness through the coupling pathways. They implicate sites for mutagenesis in model proteins and are essential for correlation of myosin functional alteration to phenotype. Myosin MD simulation provides complementary insights into how coupling pathways perform. MD introduces the causality test identifying source, path, and termination of coupling networks in sequential time that is an integral part of the competent motor. Causality testing applied to tryptophan nucleotide sensitivity has converged with experimental findings from a tonic smooth muscle myosin to suggest tryptophan nucleotide sensitivity could disconnect from lever arm movement in native myosin. A new experimental causal rotation/displacement metric, quantifying completion of a productive myosin cycle, will correlate myosin lever arm rotation with displacement of a bound actin filament (F-actin) in an in vitro assay. The two-molecule technique utilizes a green fluorescent protein (GFP) on myosin and nanometer resolution localization of a fluorescent probe bound to F-actin. Myosin variants that are, adapted to specialize function, implicated in human disease, or sourced in population diversity, are mined for insight into functional divergence. MD simulation introduces causality to characterize myosin coupling networks and produces experimentally testable hypotheses. A causal two-molecule assay tests completion of a productive myosin cycle and characterizes myosin´s ability to displace actin. These analytical tools are next-generation methods addressing transduction and motility in muscle myosin. Skeletal myosin is the motor in muscle powering contraction. Its ability to convert chemical energy to useful movement is fundamental to our ability to lead happy and productive lives. The proposed research promotes understanding of its design for energy conversion shaping approaches for how to repair an ailing motor and how to adapt it to applications where muscle productivity is limiting human potential
Keywords: Abbreviations; acronyms; Actins; Active Sites; Actomyosin; Address; Affect; Amino Acid Substitution; Amino Acids; analytical tool; Aorta; Area; arm; ATP Hydrolysis; ATP phosphohydrolase; ATP-G-actin; base; Binding (Molecular Function); Binding Sites; Biological Assay; Cardiac; cell motility; Chemicals; Chickens; Circular Dichroism; Coupled; Coupling; Data; density; design; Dictyostelium discoideum; Disease; Etiology; Exercise Physiology; F-Actin; Fluorescence; Fluorescence Microscopy; Fluorescent Probes; Free Energy; Freedom; Goals; Green Fluorescent Proteins; H-Meromyosin; Head; Health; Human; human disease; in vitro Assay; insight; Label; Lead; Learning; Light; Link; Lysine; Mediating; Methods; Metric; Microfilaments; Microscopy; Mining; Modeling; Modification; Molecular Conformation; molecular dynamics; Molecular Motors; Motor; Movement; Muscle; Mutagenesis; mutant; Mutation; Myopathy; Myosin ATPase; Myosin Heavy Chains; Myosin Light Chain Kinase; Myosin Light Chains; Myosin Regulatory Light Chains; Myosin S-1; nanometer; next generation; Nucleotides; Occupations; Pathology; Pathway interactions; Peptides; Phenotype; Play; Population; Positioning Attribute; Power stroke; Probability; Productivity; Protein Isoforms; Proteins; Recombinant Proteins; Relative (related person); repaired; Research; Resolution; Rhodamine; Role; Rotation; sensor; Shapes; simulation; Site; skeletal; Smooth Muscle Myosins; Sorting - Cell Movement; Source; Structure; Surface; System; Techniques; Testing; Thermodynamics; Time; Translating; Translations; transmission process; Tryptophan; Variant; Work
Relevance: Skeletal myosin is the motor in muscle powering contraction. Its ability to convert chemical energy to useful movement is fundamental to our ability to lead happy and productive lives. The proposed research promotes understanding of its design for energy conversion shaping approaches for how to repair an ailing motor and how to adapt it to applications where muscle productivity is limiting human potential
Project start date: 2002-12-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01AR049277-08 (2011): $323112
REGULATION OF REV-ERBALPHA AND REV-ERBBETA FUNCTION OF HEME
P Thomas, Professor
Scripps Research Institutecity: La Jolla country: United States (us)
Grant 5R01DK080201-05 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Metabolic diseases associated with aberrant metabolism of carbohydrates and lipids are the cause of significant morbidity and mortality in older people in Western Society. Several members of the nuclear receptor superfamily regulate the expression of key genes involved in regulation of carbohydrate and lipid metabolism in response to their ligands, which include fatty acids, bile acids, cholesterol metabolites, steroid hormones, and lipophilic vitamin derivatives. Recently, the ligand for a pair of related orphan nuclear hormone receptors that regulate lipid metabolism, rev-erb1 and rev-erb2, was identified. The long term objective is to determine the role of this ligand, the porphyrin heme, in regulation of the activity of the rev-erbs. Our organizing hypothesis is heme is a key ligand regulating rev-erb1/2 function in regulation of genes controlling lipid metabolism and differentiation by modulating the receptors´ affinity for corepressors. The hypothesis will be tested in the following specific aims Specific Aim 1 will determine the effect of heme on regulation of transcription by rev-erbs as well as the effect of heme on corepressor recruitment by the receptors. Specific Aim 2 will determine the specificity of heme for rev-erb1/rev-erb2 using biochemical and cell-based approaches. Specific Aim 3 will determine if heme plays an important role in rev-erb signaling during physiological processes. These studies are essential for our understanding how ligands may coordinate rev-erb regulated metabolism, and more generally, how metabolic pathways are regulated by the external environment such as nutrient status. Since nuclear hormone receptors characterized as ligand-regulated have been definitively shown to be effective targets for the development of pharmaceuticals, we predict that our proposed studies may provide the basis for novel therapeutics targeting rev-erb1 and rev-erb2 for treatment of metabolic disorders. Metabolic diseases associated with aberrant metabolism of carbohydrates and lipids are the cause of significant morbidity and mortality in older people in Western Society. We propose to characterize the role of a novel ligand, the porphyrin heme, in regulation of rev-erb1 and rev-erb2--two orphan nuclear hormone receptors that regulate the expression of key genes involved in lipid metabolism. Since nuclear hormone receptors characterized as ligand-regulated have been definitively shown to be effective targets for the development of pharmaceuticals, we predict that our proposed studies may provide the basis for novel therapeutics targeting rev-erb1 and rev-erb2 for treatment of metabolic disorders. (this is a sentence repeated from 7 lines up-I don´t know whose mistake it is, but it should probably be deleted either way)
Keywords: Address; adipocyte differentiation; Affinity; Aging; Agonist; Amino Acids; Aminolevulinic Acid; Atherosclerosis; base; Bile Acids; Binding (Molecular Function); Biochemical; carbohydrate metabolism; Cells; Cholesterol; Circadian Rhythms; Degradation Pathway; Development; Diabetes Mellitus; Disease; Dissociation; Drug Delivery Systems; Dyslipidemias; Environment; Fasting; Fatty Acids; feeding; Gases; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Heme; heme receptor; Hepatocyte; Human; human disease; Inflammation; Ligand Binding Domain; Ligands; lipid biosynthesis; lipid metabolism; Lipids; Malignant Neoplasms; member; Metabolic Diseases; Metabolic Pathway; Metabolism; Morbidity - disease rate; Mortality Vital Statistics; myogenesis; new therapeutic target; Non-Insulin-Dependent Diabetes Mellitus; novel; Nuclear Hormone Receptors; Nuclear Receptors; Nutrient; Obesity; Orphan; Pharmacologic Substance; Physiological; Physiological Processes; Play; Porphyrins; Property; receptor; Regulation; response; Role; Signal Transduction; Societies; Specificity; steroid hormone; Testing; Transcription Repressor/Corepressor; Transcriptional Regulation; Vitamins
Project start date: 2008-04-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PAS-07-267
5R01DK080201-05 (2011): $388120
5R01DK080201-04 (2010): $385110
DEVELOPMENT OF AN HTS ASSAY TO IDENTIFY FXR ANTAGONISTS
P Thomas, Professor
Scripps Research Institutecity: La Jolla country: United States (us)
Grant 1R21NS073047-01 from Roadmap Initiative, Office Of The Director
Abstract: Members of the human nuclear hormone receptor (NR) superfamily serve as receptors for steroids, thyroid hormones, retinoids, oxysterols, fatty acids, and bile acids. Nearly all of the NRs with identified ligands have been successful targets for drugs treating a variety of diseases including diabetes, dyslipidemia, inflammation, and cancer. FXR is a NR that functions as a physiological receptor for bile acids. FXR plays a critical role in bile acid homeostasis as well as glucose and lipid metabolism. FXR has been implicated as a drug target for the treatment of dyslipidemia (atheroscelerosis), diabetes, and gallstones. Although a few synthetic agonists have been identified for FXR, no selective antagonists have yet been characterized. Thus, the chemical tools available to characterize this receptor are limited. The proposed research is focused on development of assays to identify FXR antagonists that can be used as chemical tools to fully characterize the biological function of FXR as well as to validate this receptor as a potential drug target. In order to develop the assays required for identification of FXR antagonists the following specific aims will be addressed (1) Develop and validate a biochemical assay to detect FXR antagonists in a high-throughput screen format.; (2) Develop and validate secondary assays for the purpose of characterizing antagonist "hits" identified in an FXR high throughput screen; and (3) Perform a validating screen of the FXR assay flow scheme using the LOPAC 1280 chemical library. This proposal focuses on development of screening assays to identify specific FXR antagonists. FXR is a nuclear receptor that functions as a physiological receptor for bile acids. No selective FXR antagonists currently exist and identification of antagonists will allow for characterization of the role of this receptor in regulation of metabolism
Keywords: Address; Agonist; assay development; Bile Acids; Biochemical; Biological Assay; Biological Process; Chemicals; Cholelithiasis; Development; Diabetes Mellitus; Disease; Drug Delivery Systems; Dyslipidemias; Fatty Acids; Glucose; high throughput screening; Homeostasis; Human; Inflammation; Ligands; lipid metabolism; Malignant Neoplasms; member; Metabolism; Nuclear Hormone Receptors; Nuclear Receptors; Physiological; Play; receptor; receptor function; Regulation; Research; Retinoids; Role; Scheme; Screening procedure; small molecule libraries; Steroid Receptors; success; Thyroid Hormones; tool
Relevance: This proposal focuses on development of screening assays to identify specific FXR antagonists. FXR is a nuclear receptor that functions as a physiological receptor for bile acids. No selective FXR antagonists currently exist and identification of antagonists will allow for characterization of the role of this receptor in regulation of metabolism
Project start date: 2010-09-27
Project end date: 2012-08-31
Budget start date: 27-SEP-2010
Budget end date: 31-AUG-2012
PFA/PA: PAR-08-024
1R21NS073047-01 (2010): $194500
TRANSLATING EFFICACY INTO EFFECTIVENESS OF INSECTICIDE-TREATED NETS (ITNS)
P Thomas, Assistant Professor
Tulane University Of Louisianacity: New Orleans country: United States (us)
Grant 5R18CK000102-03 from Office Of Public Health Research (ophr) Fmo/ Pgo/miso/maso Users
Abstract: Insecticide-treated bed nets (ITNs) have been shown to significantly reduce malaria related morbidity and all cause child mortality across a range of transmission settings. Zambia has recently launched an unprecedented scale-up of free ITN distribution with the target of distributing 3 million long-lasting ITNs by the end of 2007. However, the impact of ITNs on preventing malaria morbidity and mortality will be minimized if they are not properly and consistently used, especially among children and pregnant women. Our long-term goal is to provide public health scientists and officials with an effective intervention to optimize ITN uptake and use among children and pregnant women as they become more widely available through the scale-up of national distribution programs. It is hypothesized that a village-based interpersonal communication (IPC) intervention will increase ITN use among households already possessing them within the context of a national ITN distribution program currently underway in Zambia. The focus of this application is to 1) test if a village based IPC intervention increases the proportion of children using ITNs within households possessing them within the context of a large-scale ITN distribution program in the Luangwa District of Zambia; 2) determine the costs associated with achieving such increased ITN use; and 3) identify household, community and policy-level factors that facilitate or impede ITN use among children. A group randomized controlled trial will be used to assess the effectiveness of the IPC intervention at increasing ITN use among children within households possessing at least one ITN, relative to children within households possessing at least one ITN within non-IPC intervention villages in the Luangwa District of Zambia. The primary outcome measure will be the proportion of children under five years old using an ITN within households possessing at least one ITN. The IPC intervention will be delivered by community health workers face-to-face in villages, and will focus primarily on 1) repeated demonstrations of proper ITN deployment and use; and 2) written, verbal and video communication as to the health-related benefits of ITNs to children. An incremental cost-effectiveness analysis will be conducted to determine the ratio of costs to effectiveness of the IPC intervention at increasing ITN use relative to the control of non-IPT villages. Immediate ways that our research will have a direct and significant scientific and societal impact include 1) Our IPC activities to increase ITN use will provide a basis for determining when, where and what types of messages should be used to achieve the greatest impact on ITN use in similar setting in Africa; 2) Positive results can potentially lead to the development of behavioral interventions strategies to increase adoption of other efficacious malaria control interventions in Africa; and 3) Our project emphasizes the identification of impediments and facilitators to ITN adherence and the translation of results into public health policy; the methods employed can serve as a model to promote interdisciplinary approaches for research and problem solving in Africa
Project start date: 2007-09-30
Project end date: 2011-09-29
Budget start date: 30-SEP-2009
Budget end date: 29-SEP-2011
PFA/PA: RFA-CD-07-005
5R18CK000102-03 (2009): $449803
IN SITU SENSING OF SINGLE MYOSIN FUNCTION IN HYPERTROPHY DISEASE
P Thomas, Consultant
Mayo Cliniccity: Rochester country: United States (us)
Grant 5R01HL095572-02 from National Heart, Lung, And Blood Institute
Abstract: Genetic screening has detected abundant mutations in sarcomeric proteins elucidating basic causes for disease and identifying targets for individualized medicine when a functional deficit on the protein level can be identified. The project focuses on the molecular motor myosin and its regulation using various approaches for the expression, dynamical characterization, and structural visualization of the protein in its native and mutated forms. The goal is to decipher the role individual mutations play in modifying native myosin function. Myosin performs ATP free energy transduction into mechanical work by coordinating ATP hydrolysis at the active site, actin affinity modulation at the actin binding site, and the lever-arm power stroke, via allosteric transduction pathways operating in a time ordered sequence. Energy transduction is the definitive systemic feature of myosin and a working model for native transduction allocates specific functions to structural domains within the motor beginning with ATP hydrolysis in the active site and ending in a power stroke rotating a lever- arm domain in the motor through ~70 degrees in the crowded environment of the muscle tissue. The cardiac myosin heavy chain (MHC) and both of its light chains (MLCs) harbor familial hypertrophic cardiomyopathy (FHC)-linked mutations. MHC mutants are hypothesized to disrupt specific transduction pathways. Evolutionarily conserved allosteric connectivity prediction identifies residues in MHC forming the transduction pathway. Transduction pathway residues that are also FHC-linked mutation sites identify the MHC candidate mutants affecting transduction. Several MLC mutants are hypothesized to impact lever-arm structural stability influencing lever-arm dynamics and effectiveness. Myosin modified by a disease-linked MHC or MLC candidate mutation is subjected to in vitro and in situ experiments to determine how the mutations impact, the functional domains in MHC operating in a working model for native transduction, or the lever-arm stability provided by the MLC. A single molecule experiment detecting lever-arm rotary movement is especially pertinent because it is applicable to myosin in the native crowded environment of the muscle fiber. Myosin regulatory light chain (RLC) may have special significance because it is partially phosphorylated at Ser15 in normal cardiac tissue. Phosphorylation apparently affects myosin calcium regulation while in the muscle tissue and myosin duty ratio in vitro within single myosin motors. In the latter case, RLC conformation modulation by phosphorylation must impact myosin function related to strong actin binding. RLC crystallization and structure determination will investigate the structural basis of RLC regulation of myosin as well as the impact of FHC-linked mutations on RLC structure. Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by an enlarged heart. It affects 1 in 500 persons and is a cause of sudden cardiac death in the young. Genetic mutations affecting protein structure and function in the heart are linked to FHC. The project goal is to associate the mutation with the specific protein function affected to identify basic causes for disease and targets for individualized medicine. The proposed research applies promising new computational and experimental approaches for assessing how disease implicated mutations change the motor powering contraction
Keywords: 3-Dimensional; Actins; Active Sites; Affect; Affinity; arm; ATP Hydrolysis; base; Binding (Molecular Function); Binding Sites; Biological Assay; Calcium; Cardiac; Cardiac Myosins; Cardiomegaly; Cardiomyopathy, Hypertrophic, Familial; cell motility; Complex; Crowding; Crystallization; Data; Death, Sudden, Cardiac; Detection; dipole moment; Disease; disease phenotype; Docking; Effectiveness; Electrons; Environment; Fluorescence Polarization; Free Energy; Gene Mutation; Genetic Screening; Goals; H-Meromyosin; Heart; Hypertrophy; Image; Imagery; In Situ; In Vitro; Individual; inorganic phosphate; Kinetics; Label; Light; Link; Location; Measures; Mechanics; Mediating; Medicine; Metric; Microscopic; Modeling; Molecular; Molecular Conformation; Molecular Motors; Monitor; Motor; Movement; Muscle; Muscle Fibers; Muscle function; Muscle Rigidity; mutant; Mutate; Mutation; Myocardium; Myosin ATPase; Myosin Heavy Chains; Myosin Regulatory Light Chains; Myosin Type II; papillary muscle; Pathway interactions; Peptides; Persons; Phosphorylation; Play; Positioning Attribute; Power stroke; Production; protein function; protein structure function; Proteins; public health relevance; Recombinants; reconstruction; Regulation; Relative (related person); Research; research study; Role; Rotation; single molecule; Single Nucleotide Polymorphism; Site; Smooth muscle (tissue); src Homology Region 2 Domain; Structure; System; Testing; Time; Tissues; Torque; Translating; Translations; Tryptophan; Work
Relevance: In Situ Sensing of Single Myosin Function in Hypertrophy Disease Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by an enlarged heart. It affects 1 in 500 persons and is a cause of sudden cardiac death in the young. Genetic mutations affecting protein structure and function in the heart are linked to FHC. The project goal is to associate the mutation with the specific protein function affected to identify basic causes for disease and targets for individualized medicine. The proposed research applies promising new computational and experimental approaches for assessing how disease implicated mutations change the motor powering contraction
Project start date: 2010-07-15
Project end date: 2014-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01HL095572-02 (2011): $383339
NON-APOPTOTIC ACTION OF CASPASES IN PLURIPOTENT EMBRYONIC STEM CELLS
P Thomas, Assistant Professor
Baylor College Of Medicinecity: Houston country: United States (us)
Grant 5R01GM077442-04 from National Institute Of General Medical Sciences
Abstract: Embryonic stem (ES) cells are pluripotent and can expand in vitro without any apparent limits, while retaining their ability to become any type of cell in the body. The long-term goal of this proposal is to link the molecular mechanisms of programmed cell death to those underlying ES cell renewal and differentiation, with a view toward accelerating the clinical introduction of ES cell regenerative medicine. In my preliminary studies, I found that caspase-3, an important mediator of programmed cell death, has an unexpected role in controlling ES cell fate. I demonstrate an increase of caspase-3 activity upon induction of differentiation and show that caspase-3 can directly cleave the Nanog transcription factor, leading to rapid loss of this core pluripotency- related protein and subsequent ES cell differentiation it typically mediates. These results suggest that caspase- 3 and perhaps other key components of the programmed cell death pathway may have an integral role in the regulation of ES cell renewal/differentiation. The central hypothesis of this proposed work is that classical mediators of programmed cell death, especially caspase-3, also mediate the fate decisions affecting pluripotent stem cells. In Aim 1 I will dissect the functional roles of caspase-3 and it´s activating caspase in the fate of ES cells. In Aim 2 I will modulate caspase activity in ES cells and assess the effects on self-renewal, differentiation and programmed cell death. I will also address the question of whether the differentiation-promoting activity of caspase-3 in ES cells is due to an instructive or selective signaling and elucidate if caspase activity provides a specific signal to differentiate or simply promotes differentiation in general. In Aim 3 I will assess the importance of caspase-3-mediated cleavage of Nanog in ES cell differentiation. I consider the transcription factor Nanog to be a paradigm for other potential caspase targets in ES cells, so that my findings for this regulatory protein could well extend to other transcriptional pathways involved in ES cell differentiation. Results of the experiments described in this proposal are expected to provide insight into the pleiotropic effects of caspases in pluripotent stem cells. Thus, specific pharmacological alteration of caspases may be useful not only for modulating apoptosis, but also for directing stem cell fate. The involvement of caspases in nonapoptotic pathways suggests that efforts to block apoptosis via caspase inhibition could have much broader consequences than initially thought. The ability of embryonic stem cells to remain undifferentiated in culture while retaining the ability to become any cell within the human body make them an invaluable tool for use in transplant medicine, drug discovery, and understanding basic developmental biology. Results of the experiments described in this proposal are expected to provide insight into the pleiotropic effects of the cell death enzyme caspase on the differentiation process of embryonic stem cells. Specific pharmacological alteration of caspases may be useful not only for modulating programmed cell death, but also for directing stem cell fate
Keywords: Address; Affect; Apoptosis; Apoptotic; caspase; caspase-3; caspase-9; Cell Death; cell type; Cells; Cleaved cell; Clinical; Development; Developmental Biology; Disease; drug discovery; embryonic stem cell; Enzymes; genetic regulatory protein; Goals; Human body; In Vitro; insight; Knock-out; Link; loss of function; Measures; Mediating; Mediator of activation protein; Molecular; mutant; Pathway interactions; Phenotype; pluripotency; Pluripotent Stem Cells; Process; Proteins; public health relevance; Regenerative Medicine; regenerative therapy; Regulation; research study; Resistance; Role; self-renewal; Signal Transduction; small hairpin RNA; Small Interfering RNA; stem cell differentiation; stem cell division; stem cell fate; System; Testing; tool; transcription factor; transplantation medicine; Undifferentiated; Work
Project start date: 2008-08-01
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01GM077442-04 (2011): $300891
GENETICS MANAGEMENT AND ANALYSIS TOOLS: GEMS
P Thomas
Scisio Genetics, Inc.city: Seattle country: United States (us)
Grant 5R42RR018669-04 from National Center For Research Resources
Abstract: During Phase I, this project successfully implemented a Genetics Management System (GeMS) in partner labs for testing and requirements gathering. During Phase II, the project will expand these efforts towards additional labs and will implement new functionalities into GeMS, increasing the data-managing and data sharing capabilities of GeMS. Our Phase I accomplishments include 1) a revision of the overall architecture for GeMS, 2) establishing a functional software development methodology, 3) the installation, requirements gathering, and testing of GeMS in five laboratories, 4) the identification of a number of specific needs from our partner labs for future implementation, 5) an accounting of cost savings from the use of GeMS, 6) the development of new analytical tools that meet needs of the relevant area of biomedical research, 7) substantial new programming completed implementing several GeMS core components and new service modules, and 8) the identification of additional academic laboratories for new deployments. The overall goal of this Phase II application is to provide methods for researchers with improved ability to generate, organize, analyze, and share data and metadata. To this end, we propose to accomplish the following specific aims, 1) To improve existing tools and implement new solutions for data analysis, 2) To extend GeMS to support new data models, 3) To improve the functionality of GeMS towards interaction with other systems, and 4) To expand the number of GeMS deployments. From these efforts we propose to engage the development and application of new biocomputing tools or technologies for a particular area(s) of scientific opportunity in biomedical research." In that regard, we have built and propose to further develop tools for data acquisition, archiving, querying, retrieval, visualization, integration, and management, web-based linkage tools for data sharing and tools for electronic communication, and new analytical tools for interpretation of complex sequence trace data. In Phase I we formed a cross-disciplinary collaboration with state of the art software development methods to produce products that are relevant to this scientific area and are evolvable, scalable, extensible, and interoperable computational resources. This project spans the interface of biomedical research and biomedical computational science and technology. It combines senior software engineers from industry, software engineers with biomedical backgrounds, and an active biomedical user laboratory defining requirements, forming unique cross-disciplinary collaborations between state of the art computer science applications and state of the art genomic/genetic methods and approaches
Keywords: Accounting; Analysis, Data; analytical tool; Architecture; Archives; Area; Arts; Basic Research; Basic Science; bio-computation; bio-computing; biocomputing; biomedical computation; Biomedical Computing; Biomedical Research; body movement; Client; Collaborations; commercialization; Communication; Complex; Computational Science; computer program/software; Computer Programs; computer science; Computer software; Computer Software Development; Computer Software Engineering; computing resources; Cost Savings; Data; data acquisition; Data Analyses; data modeling; Data Set; Dataset; develop software; developing computer software; Development; Electronics; Engineering / Architecture; Engineering, Software; fundamental research; Future; Genetic; Genetic screening method; genetic testing; Genomics; Genotype; Goals; Grant; Imagery; improved; Industry; innovate; innovation; innovative; instrumentation; Instrumentation, Other; Investigators; Laboratories; Maintenance; Maintenances; meetings; Metadata; Method LOINC Axis 6; Methodology; Methods; Motivation; Movement; Nature; NIH Program Announcements; On-Line Systems; online computer; Online Systems; Phase; Phase Transition; Process; Program Announcement; programs; Programs (PT); Programs [Publication Type]; Research; Research Personnel; Research Resources; Researchers; Resources; Retrieval; Saving, Cost; Science; Services; sharing data; Side; Small Business Technology Transfer Research; Software; software development; Software Engineering; Solutions; STTR; System; System, LOINC Axis 4; Technology; Testing; Time; tool; Visualization; web based; Writing
Project start date: 2003-07-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
PFA/PA: PAR-06-089
5R42RR018669-04 (2009): $558319
Sponsored Links Excellgen http://Excellgen.com
EFFECTS OF GLYCEMIC CONTROL ON IMMUNITY
P Thomas, Director, Peds Critical Care
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5R01HL097361-03 from National Heart, Lung, And Blood Institute
Abstract: Cardiopulmonary bypass (CPB) is necessary to repair complex congenital heart disease (CHD), but also contributes to the morbidity and mortality in children surviving surgical repair. Following CPB, release of both stress-related hormones and pro-inflammatory cytokines contribute to post-operative organ dysfunction by mediating endothelial cell-leukocyte adhesion and vascular inflammation. Furthermore, pro inflammatory cytokines and stress hormones may mediate insulin resistance and contribute to the high rate of hyperglycemia in children after CPB. Increasingly, there is evidence to suggest that hyperglycemia negatively impacts organ function, acquisition of nosocomial infections, intensive care unit (ICU) length of stay, and mortality in various critically ill patient populations-but particularly in post-operative cardiovascular patients. A collaborative, randomized controlled trial (RCT) of infants undergoing CPB for CHD is being conducted to determine whether tight glycemic control in the post-operative time frame can alter these detrimental outcomes. Hyperglycemia and insulin have been shown to impact the production of cytokines in human and animal models of critical illnesses; however, the mechanism(s) by which tight glycemic control affects this host immune response remains unknown. Notably, circulating dendritic cells (DCs) play a key role in linking the innate and adaptive immune responses and are significantly decreased by inflammatory insults. This loss of DCs has been attributed to increased pro inflammatory cytokines and altered cellular energetics and has been shown to increase the host´s risk of infection. Furthermore, we´ve observed significant attenuation of pro inflammatory cytokine expression from circulating monocytes post- CPB that we propose is due to epigenetically-mediated changes on the promoter regions of canonical type 1 and type 2 cytokines. The current RCT of tight glycemic control in pediatric cardiac surgical patients provides the opportunity to explore potential immunobiologic mechanisms that reduce pro inflammation, organ dysfunction and development of infection. In the context of this trial, we aim to test the hypothesis that tight glycemic control during the post-operative period will modify the infant´s immune response resulting in decreased pro-inflammation, increased circulating DCs and modified epigenetic signature thereby decreasing organ dysfunction and post-operative infections. Using a machine that enables blood to bypass the heart and lungs, so called, cardiopulmonary bypass (CPB), is needed stop the heart and keep it still during operations to repair complicated anatomic abnormalities babies are often borne with termed "congenital heart disease" (CHD), This strategy enables life saving surgeries, but also contributes to organ injury or failure and at times the death experienced by children surviving this initial surgical repair. After CPB, release of both stress-related hormones and inflammatory molecules the body makes contribute to blood vessel inflammation and post-operative organ dysfunction. Furthermore, these molecules and hormones may mediate insulin resistance and contribute to the high rate of high blood sugars (called "hyperglycemia") often seen in children after CPB. We believe that hyperglycemia negatively impacts organ function, increases the risk of getting an infection during the recovery period in the hospital, prolongs the time in the intensive care unit in very sick patients, but especially in patients following heart surgery. A collaborative, NIH-sponsored trial of infants undergoing CPB for CHD is being performed to determine whether tightly controlling the blood sugar in the post- operative time frame can alter these outcomes. Hyperglycemia and its main therapy, insulin, have been shown to impact the production of these problematic molecules in both humans and animals who are critically ill; however, the mechanism by which this approach affects the immune response remains unknown. Notably, a particular cell type that circulates in the blood stream called dendritic cell (DCs) play an important role in optimizing the function of the immune system and these cells are significantly decreased by inflammation as occurs after infections and probably CPB. This loss of DCs has been attributed to increased pro inflammatory molecules and altered cellular energy states and most importantly has been shown to increase the risk of getting an infection. Furthermore, we´ve already observed a significant lowering of pro inflammatory cytokine expression from circulating cells after CPB that we think may be due to unique changes on the parts of the DNA that determines how a molecule will be made or not. The current trial of tight glycemic control in pediatric cardiac surgical patients provides the opportunity to explore potential ways to reduce pro inflammation, organ dysfunction and development of infection. (End of )
Keywords: ing; Adhesions; Affect; anakinra; Anesthetics; Animal Model; Animals; Anti-inflammatory; Anti-Inflammatory Agents; Attenuated; attenuation; Biological Assay; Blood; Blood Glucose; Blood Vessels; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cardiovascular system; Cell Count; cell type; Cells; Cessation of life; Characteristics; Child; Childhood; chromatin immunoprecipitation; cohort; Congenital Heart Defects; congenital heart disorder; Control Groups; Critical Illness; cytokine; Cytokine Gene; Deformity; Dendritic Cells; Development; DNA; Endothelial Cells; Epigenetic Process; experience; Failure (biologic function); Fluid Balance; Functional disorder; Gene Expression; Genes; glycemic control; Health; Heart; Hormones; Hospitals; Hour; Human; Hyperglycemia; Immune response; Immune system; Immunity; Immunologics; improved; Incidence; Infant; Infection; Inflammation; Inflammatory; Injury; Insulin; Insulin Resistance; Intensive Care Units; Interleukin-10; Interleukin-12; Interleukin-12 Gene; Interleukin-13; Interleukin-6; Interleukin-8; Interleukins; Length of Stay; Leukocytes; Life; Link; Measures; Mechanical ventilation; Mediating; Methodology; monocyte; Morbidity - disease rate; Mortality Vital Statistics; Myelogenous; Nosocomial Infections; operation; Operative Surgical Procedures; Organ; Outcome; Parents; patient population; Patients; Pattern; peripheral blood; Phenotype; Plasma; Play; Postoperative Period; Production; Promoter Regions (Genetics); Promotor (Genetics); Randomized; Randomized Controlled Trials; Recovery; Repair Complex; repaired; Resolution; response; Risk; Role; standard of care; Stream; Stress; Technology; Testing; Time; TNF gene; United States National Institutes of Health; Vascular Diseases; vascular inflammation
Relevance: Narrative Using a machine that enables blood to bypass the heart and lungs, so called, cardiopulmonary bypass (CPB), is needed stop the heart and keep it still during operations to repair complicated anatomic abnormalities babies are often borne with termed "congenital heart disease" (CHD), This strategy enables life saving surgeries, but also contributes to organ injury or failure and at times the death experienced by children surviving this initial surgical repair. After CPB, release of both stress-related hormones and inflammatory molecules the body makes contribute to blood vessel inflammation and post-operative organ dysfunction. Furthermore, these molecules and hormones may mediate insulin resistance and contribute to the high rate of high blood sugars (called "hyperglycemia") often seen in children after CPB. We believe that hyperglycemia negatively impacts organ function, increases the risk of getting an infection during the recovery period in the hospital, prolongs the time in the intensive care unit in very sick patients, but especially in patients following heart surgery. A collaborative, NIH-sponsored trial of infants undergoing CPB for CHD is being performed to determine whether tightly controlling the blood sugar in the post- operative time frame can alter these outcomes. Hyperglycemia and its main therapy, insulin, have been shown to impact the production of these problematic molecules in both humans and animals who are critically ill; however, the mechanism by which this approach affects the immune response remains unknown. Notably, a particular cell type that circulates in the blood stream called dendritic cell (DCs) play an important role in optimizing the function of the immune system and these cells are significantly decreased by inflammation as occurs after infections and probably CPB. This loss of DCs has been attributed to increased proinflammatory molecules and altered cellular energy states and most importantly has been shown to increase the risk of getting an infection. Furthermore, we´ve already observed a significant lowering of proinflammatory cytokine expression from circulating cells after CPB that we think may be due to unique changes on the parts of the DNA that determines how a molecule will be made or not. The current trial of tight glycemic control in pediatric cardiac surgical patients provides the opportunity to explore potential ways to reduce proinflammation, organ dysfunction and development of infection
Project start date: 2009-06-01
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-HL-08-001
5R01HL097361-03 (2011): $390726
GENOMICS OF MYOCARDIAL TRANSCRIPTION FACTORS IN CARDIAC REMODELING
P Thomas
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 5R01HL088577-05 from National Heart, Lung, And Blood Institute
Abstract: Cardiac remodeling is a central feature of human heart failure and shows substantial variation in human subjects. A decade of research in murine models and research in humans performed by the Principal Investigator show that a discreet set of cardiac transcription factors integrate stress signals to cause cardiac remodeling. Our central hypothesis is that common genetic variation in a core set of cardiac transcription factors (MEF2, NKX, NFAT, GATA, FOX) is in large part responsible for the variable course of cardiac remodeling in humans. We will address this hypothesis by performing SNP- and haplotype-based association studies of candidate transcription factors in two existing cohort studies that capture the common phenotypes of remodeling encountered in clinical practice. In Aim 1 we will test the hypothesis that variation in candidate transcription factors is associated with concentric cardiac remodeling in the Chronic Renal Insufficiency Cohort study (CRIC), a large cohort with a high prevalence of concentric remodeling. In Aim 2 we will perform similar analyses in the Penn Heart Failure Study, a large single-center cohort initiated by with a high prevalence of eccentric remodeling. In aim 3 we will collaborate with an expert molecular biologist at Penn, Dr. Edward Morrisey, to determine the mechanisms by which the observed risk variants alter transcription factor function using in vitro techniques. This application uses genomic approaches to study cardiac transcription factors directly in human subjects with common forms of heart disease. The use of two established cohorts with large sample sizes and quantitative echocardiography will provide the phenotypic data necessary to address our hypotheses definitively, and will capitalize on investments already made in establishing large, well-phenotyped cohorts. By focusing on factors of central importance in animal models that have not been adequately studied in humans, our findings will translate years of basic research into a mechanistic understanding of human cardiac remodeling. Most importantly, we expect to determine and validate genomic predictors of cardiac remodeling that may have clinical applications as tools to predict prognosis and to select high-risk patients for aggressive therapy
Keywords: activating transcription factor; Address; aggressive therapy; Animal Model; base; Basic Science; Biochemical; Bioinformatics; Biomechanics; Cardiac; Cardiovascular Diseases; Cessation of life; Chronic Kidney Insufficiency; Clinical; clinical application; clinical practice; cohort; Cohort Studies; Collaborations; Complex; Cross-Sectional Studies; Data; Disease; Echocardiography; Event; follow-up; Functional disorder; Gene Expression; genetic variant; Genomics; Haplotypes; Heart; Heart Diseases; Heart failure; Heart Transplantation; High Prevalence; high risk; Hospitalization; Human; human subject; In Vitro; Incidence; Individual; Injury; insight; Investments; Kidney; Kidney Failure; Left; Left Ventricular Hypertrophy; Left Ventricular Mass; Measures; Mediating; Mediator of activation protein; Methodology; Modeling; Molecular; Molecular Genetics; Mus; Myocardial; Myocardium; novel; Observational Study; Outcome; outcome forecast; Pathogenesis; Pathologic; Patients; Phenotype; Population; Principal Investigator; programs; prospective; Research; Research Personnel; response; Risk; Sample Size; Signal Pathway; Signal Transduction; Stress; Systolic heart failure; Techniques; Testing; Thick; Time; tool; transcription factor; Translating; United States National Institutes of Health; Variant; Variation (Genetics); Ventricular
Project start date: 2007-08-01
Project end date: 2014-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5R01HL088577-05 (2011): $735010
MICHIGAN INSTITUTE FOR CLINICAL AND HEALTH RESEARCH (MICHR) (TL1)
P Thomas, Director, Peds Critical Care
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5TL1RR024988-05 from Office Of The Director, National Institutes Of Health
Abstract: At Michigan, we enjoy a campus rich in clinical research training programs. We have NCRR K30 and K12 programs under the same leadership. There are two other NIH K12 programs and we are the only institution to house all three RWJ clinical research training programs. Several years ago, the institutionally-funded Center for Advancement of Clinical Research (now MICHR) began to help coordinate some of these programs and also began a series of education programs aimed at both faculty and staff that filled gaps not addressed by these NIH-funded and other training programs. More recently, MICHR also recently worked with Dr. Sewon Kang to successfully compete for a Roadmap T32, aimed at giving medical, dental, nursing, and pharmacy students additional training in clinical research. Last year this new program began a second new Master´s in Clinical Research to augment and complement the longstanding and successful On Job, On Campus Master´s in Clinical Research Design and Statistical Analysis in the School of Public Health. MICHR leadership has continued to work closely with the leaders of all of the above programs, serving as members on the executive and advisory committees of these units and co-sponsoring a number of education courses and symposia. Despite many successful programs and a high existing degree of integration during our planning for the UM CTSA, we identified many present barriers or unrecognized opportunities that we felt could be addressed by a new MICHR Education Program. To train individuals who will comprise the translational research teams of the future, we feel we must not only build upon these successful programs, but entirely re-engineer the educational paradigms we use to train clinical and translational researchers. We propose an innovative program to overcome the following barriers ¿ Although all of these clinical and translational research training programs at UM are successful and fill critical needs, they focus on providing time-intensive training requiring one year or more of dedicated study and are designed primarily for physicians and other healthcare providers. o The research teams of the future will contain many healthcare providers and others who do not desire or need as intensive training; we have few programs at UM aimed at these key research team members, o Similarly, the research teams of the future need intensively trained study coordinators, data managers, etc., who are not currently being trained at UM or most universities, o Other important constituencies in the translational research teams of the future whose needs are not being adequately met with our current programs include basic scientists, patients and community members, undergraduates, and mid-career faculty. ¿ We have 68 T32 training grants at UM, most of which require some modest element of clinical research training. Often, in each department or unit, a few fellows or residents at at time get an isolated and often inadequate exposure to clinical and translational research methods and training. Not only is this harmful to the overall training of these individuals but, more importantly, it represents a missed opportunity to excite these trainees about a career in clinical and translational research. There is a need for centralized clinical and translational research education programs to meet this need and to enhance the MICHR mission of creating a community of clinical and translational researchers. ¿ Even though we have excellent mentorship programs embedded within the K30 and K12 programs, Michigan trainees and junior faculty who are not in these programs often have difficulty identifying and engaging a mentor or mentors. ¿ Success in recruiting qualified minority postdoctoral trainees is limited due to a small pool of candidates in the biomedical sciences. ¿ Our current training programs are primarily ´face-to-face´ and do not maximally leverage modern technologies to increase access to trainees and faculty, neither at UM nor at a distance. ¿ New developments in the training of clinical translational researchers often remain within the institution and do not transcend into the national scene
Keywords: Address; Advisory Committees; Basic Science; bench to bedside; career; career development; Clinical; Clinical Research; Clinical Research Curriculum Award; Collaborations; Commit; Communities; Complement; Data; Dental Students; Development; Doctor of Philosophy; Educational aspects; Elements; Engineering; experience; Exposure to; Faculty; flexibility; Fostering; Funding; Future; Grant; Health; Health Personnel; Home environment; Housing; Individual; innovation; Institutes; Institution; Institutional Review Boards; Laboratories; Leadership; Learning; Medical Students; meetings; member; Mentors; Mentorship; Methodology; Michigan; Minority; Mission; Modeling; National Center for Research Resources; novel strategies; Nursing Students; Occupations; Outcome; outreach; Patients; Pharmacy Students; Physician Scientist Award (Program); Physicians; Pilot Projects; Positioning Attribute; Postdoctoral Fellow; Program Effectiveness; programs; Public Health Schools; Qualifying; Recruitment Activity; Research; Research Design; Research Infrastructure; Research Methodology; Research Personnel; Research Training; Resources; Rewards; Science; Scientist; Series; success; symposium; Technology; Testing; Time; Training; Training and Education; Training Programs; Transcend; Translational Research; Translations; Underrepresented Minority; United States National Institutes of Health; Universities; Work
Project start date: 2007-09-17
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-RM-07-002
5TL1RR024988-05 (2011): $474156
USE OF INDUCED PLURIPOTENT STEM CELLS TO STUDY MECHANIMS OF FAMILIAL AND SPORADIC
P Thomas
Columbia University Health Sciencescity: New York country: United States (us)
Grant 5DP1OD003930-05 from Office Of The Director, National Institutes Of Health
Abstract: ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons, culminating in muscle wasting and death from respiratory failure [1-3]. The majority of ALS cases are sporadic, with 90% of patients presenting disease symptoms with no family history of ALS. The remaining 10% of ALS patients are diagnosed with familial ALS [1-3]. Approximately 25% of the familial cases of ALS are caused by mutations in the dominantly inherited gene encoding super oxide dismutase (SOD) [4]. Identification of pathogenic alleles of SOD1 has led to the production of transgenic mouse and rat models for the study of ALS [5-8]. Overproduction of pathogenic human SOD1 protein in mice and rats leads to late onset, progressive neurodegenerative disease [5, 6, 8]. Studies of the SOD1 animal models have led to the identification and study of intrinsic pathogenic characteristics of ALS motor neurons including the formation of protein aggregates, cytoskeletal abnormalities, proteasome dysfunction and increased sensitivity to cell death signals [1, 5]. Although much has been learned in these animal models of the familial disease, very little is known about the sporadic disease because of the lack of a suitable in vivo system. We propose to make use of recent advances in stem cell research [9-13] to generate and study human motor neurons in culture derived from fibroblasts donated by sporadic ALS patients. These motor neurons will be used in long term cell cultures to examine pathophysiological hallmarks of the sporadic disease, including analysis of protein aggregates, morphologically altered mitochondria, electrophysiological properties, gene expression analyses, and examination of patterns of alternative pre-mRNA splicing. If successful, these studies may provide important new mechanistic insights into sporadic ALS, and provide cell-based assays for drug screening
Keywords: ing; Alleles; Animal Model; base; Biological Assay; Cell Culture Techniques; Cell Death Signaling Process; Cells; Cessation of life; Characteristics; Diagnosis; Disease; Familial disease; Family history of; Fibroblasts; Functional disorder; Gene Expression; Genes; Human; in vivo; induced pluripotent stem cell; Inherited; insight; Learning; Mitochondria; Motor Neurons; mRNA Precursor; multicatalytic endopeptidase complex; Mus; Muscle; Mutation; Neurodegenerative Disorders; Oxides; Patients; Pattern; Preclinical Drug Evaluation; Production; Property; protein aggregate; Proteins; Rattus; Respiratory Failure; RNA Splicing; Stem Cell Research; Study models; Symptoms; System; Transgenic Mice; wasting
Project start date: 2008-09-30
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-RM-08-013
5DP1OD003930-05 (2011): $796950
PP2A REGULATION OF THE JNK MAPK PATHWAY
P Thomas, Director, Peds Critical Care
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5R01GM066839-09 from National Institute Of General Medical Sciences
Abstract: Activation of the innate immune response commonly triggers the acute pathophysiology characteristic of critical illnesses. This conserved response is necessary for host survival in the face of infections; however, if left unregulated, this proinflammation may impact organ function and host survival. A paradigm focused on proinflammation has driven recent therapeutic approaches, but with little success in ameliorating critical illnesses. Thus, a paradigm shift that places greater emphasis on understanding the counter-regulation of this biology may be necessary. It is likely that substantial immunologic dissonance exists in critically ill patients so that therapeutically targeting one end of this spectrum is unlikely to be successful. Therefore, our focus is on elucidating regulatory mechanisms that limit proinflammation, acknowledging that these can also become dysregulated resulting in the functional immunodeficiency often reported late in sepsis and multiple organ dysfunction syndrome. A canonical pathway examined in both states of dysregulation is LPS induction of tumor necrosis factor (TNF)-1 which is dependent on transcriptional and post-transcriptional regulation by MAP kinase pathways. Preliminary data shows that inhibiting PP2A activity results in augmented TNF-1 expression after LPS stimulation in a manner dependent on p38 activation. Furthermore, stimulation of cells is rapidly followed by changes in the subcellular localization, post-translational modification, and activitation of PP2A suggesting these mechanisms are crucial for targeting kinase regulation. These findings prompt the question as to whether similar mechanisms are at play in states of immune deactivation in vivo. Therefore, the central hypothesis of this proposal is that PP2A negatively regulates MAPK signaling pathways triggered by inflammatory stimuli and that this is modulated by sub-cellular localization and post-translational modifications of PP2A and regulated by the ceramide. Furthermore, we hypothesize that induction of the hyporesponsive monocyte/macrophage in vivo is modulated by increased PP2A activity. As a result, we aim to 1) determine the molecular mechanisms by which PP2A regulates endotoxin-induced TNF-1 biosynthesis in macrophages; 2) determine the composition of, post-translational modifications, and subcellular localization of PP2A following cellular activation; 3) define the contribution of TNF-1, ceramide and PP2A activation in mediating an LPS hyporesponsive macrophage phenotype; 4) define the in vivo role of PP2A in mediating a deactivated state of immune reactive cells in children subjected to a predictable inflammatory challenge. The results from these studies will provide novel insight into the functional regulatory mechanisms mediated by PP2A involving key inflammatory signaling pathways. Results should define a broader model of phosphatase regulation of inflammatory-triggered gene expression and aid in the identification of innovative strategies for modifying the timing and degree of proinflammatory gene expression. The human immune system has evolved so that patients who are afflicted with infections can mount a strong immune response, termed proinflammation, to kill and clear invading pathogens from the body. Often, this proinflammatory response is so substantial that it affects the normal physiologic functions of the individual thereby creating the need for intensive medical care because of organ failure. Unfortunately, targeting our therapies to block this response has not been very successful. We have learned that the body also mounts a response to counter proinflammation and therefore avoid this acute damage; however, this process can also become too intense causing a state of immune dysfunction through cellular deactivation. The goals of the proposed studies are to understand the molecular mechanisms by which the protein phosphatase, PP2A, regulates a typical proinflammatory pathway and to determine whether PP2A activity is responsible for the state of cellular deactivation. A combination of cellular and human studies will be used with the aim of defining a broader model by which phosphatases regulate inflammation. We also aim to identify innovative strategies for modifying the timing and degree of cellular activation and/or deactivation in states of critical illness
Keywords: Acute; Affect; Anabolism; Attenuated; attenuation; base; Binding (Molecular Function); Biology; Caring; Cell Fraction; Cell surface; Cells; Ceramides; Characteristics; Child; Clinical; Complex; Critical Illness; Critically ill children; cytokine; Data; defined contribution; DNA Polymerase II; Endotoxins; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genetic Transcription; Goals; Health; Host Defense; Human; Immune; Immune response; Immune system; Immune System Diseases; Immunologic Deficiency Syndromes; Immunologics; in vitro Model; in vivo; Individual; Infection; Inflammation; Inflammatory; innovation; insight; Invaded; Killings; Learning; Left; Ligation; Lipids; Lipopolysaccharides; Lung Injury, Acute; macrophage; Macrophage Activation; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MAPK14 gene; MAPK8 gene; Measures; Mediating; Mediator of activation protein; Medical; Messenger RNA; Methylation; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Chaperones; monocyte; mRNA Stability; Multiple Organ Failure; Natural Immunity; novel; Organ; Organ failure; Outcome; pathogen; Pathway interactions; Patients; Pattern; Peritoneal Macrophages; Phenotype; Phospholipids; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Transcriptional Regulation; Post-Translational Protein Processing; Process; Protein Dephosphorylation; Protein phosphatase; Protein Phosphatase 2A Regulatory Subunit PR53; protein protein interaction; Proteins; Puncture procedure; Regulation; Reporting; research study; response; RNA; RNA Polymerase II; Role; Sepsis; Signal Pathway; Stimulus; success; Testing; Therapeutic; Time; trafficking; transcription termination; Tumor Necrosis Factor-alpha; Untranslated Regions
Relevance: The human immune system has evolved so that patients who are afflicted with infections can mount a strong immune response, termed proinflammation, to kill and clear invading pathogens from the body. Often, this proinflammatory response is so substantial that it affects the normal physiologic functions of the individual thereby creating the need for intensive medical care because of organ failure. Unfortunately, targeting our therapies to block this response has not been very successful. We have learned that the body also mounts a response to counter proinflammation and therefore avoid this acute damage; however, this process can also become too intense causing a state of immune dysfunction through cellular deactivation. The goals of the proposed studies are to understand the molecular mechanisms by which the protein phosphatase, PP2A, regulates a typical proinflammatory pathway and to determine whether PP2A activity is responsible for the state of cellular deactivation. A combination of cellular and human studies will be used with the aim of defining a broader model by which phosphatases regulate inflammation. We also aim to identify innovative strategies for modifying the timing and degree of cellular activation and/or deactivation in states of critical illness
Project start date: 2005-01-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01GM066839-09 (2011): $273926
MICHIGAN INSTITUTE FOR CLINICAL AND HEALTH RESEARCH (MICHR) (KL2)
P Thomas, Director, Peds Critical Care
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5KL2RR024987-05 from National Center For Research Resources
Abstract: A. Overview. At Michigan, we enjoy a campus rich in clinical research training programs. We have NCRR K30 and K12 programs under the same leadership. There are two other NIH K12 programs and we are the only institution to house all three RWJ clinical research training programs. Several years ago, the institutionally-funded Center for Advancement of Clinical Research (now MICHR) began to help coordinate some of these programs and also began a series of education programs aimed at both faculty and staff that filled gaps not addressed by these NIH-funded and other training programs. More recently, MICHR also recently worked with Dr. Sewon Kang to successfully compete for a Roadmap T32, aimed at giving medical, dental, nursing, and pharmacy students additional training in clinical research. Last year this new program began a second new Master´s in Clinical Research to augment and complement the longstanding and successful On Job, On Campus Master´s in Clinical Research Design and Statistical Analysis in the School of Public Health. MICHR leadership has continued to work closely with the leaders of all of the above programs, serving as members on the executive and advisory committees of these units and co-sponsoring a number of education courses and symposia. Despite many successful programs and a high existing degree of integration during our planning for the UM CTSA, we identified many present barriers or unrecognized opportunities that we felt could be addressed by a new MICHR Education Program. To train individuals who will comprise the translational research teams of the future, we feel we must not only build upon these successful programs, but entirely re-engineer the educational paradigms we use to train clinical and translational researchers. We propose an innovative program to overcome the following barriers ¿ Although all of these clinical and translational research training programs at UM are successful and fill critical needs, they focus on providing time-intensive training requiring one year or more of dedicated study and are designed primarily for physicians and other healthcare providers. o The research teams of the future will contain many healthcare providers and others who do not desire or need as intensive training; we have few programs at UM aimed at these key research team members, o Similarly, the research teams of the future need intensively trained study coordinators, data managers, etc., who are not currently being trained at UM or most universities, o Other important constituencies in the translational research teams of the future whose needs are not being adequately met with our current programs include basic scientists, patients and community members, undergraduates, and mid-career faculty. ¿ We have 68 T32 training grants at UM, most of which require some modest element of clinical research . training. Often, in each department or unit, a few fellows or residents at at time get an isolated and often inadequate exposure to clinical and translational research methods and training. Not only is this harmful to the overall training of these individuals but, more importantly, it represents a missed opportunity to excite these trainees about a career in clinical and translational research. There is a need for centralized clinical and translational research education programs to meet this need and to enhance the MICHR mission of creating a community of clinical and translational researchers. ¿ Even though we have excellent mentorship programs embedded within the K30 and K12 programs, Michigan trainees and junior faculty who are not in these programs often have difficulty identifying and engaging a mentor or mentors. ¿ Success in recruiting qualified minority postdoctoral trainees is limited due to a small pool of candidates in the biomedical sciences. , ¿ Our current training programs are primarily ´face-to-face´ and do not maximally leverage modern technologies to increase access to trainees and faculty, neither at UM nor at a distance. ¿ New developments in the training of clinical translational researchers often remain within the institution and do not transcend into the national scene. The Education and Mentoring Program of MICHR (hereafter referred to as the Education Program or EP) will design new educational programs and transform existing programs to meet the diverse needs of the broader clinical and translational research community. By utilizing innovative methods in interdisciplinary education and effective mentoring to facilitate the career development, we propose to establish a coordinated curriculum in translational research. The MICHR EP curriculum will 1) increase the number of professionals receiving combined training in basic and clinical research through expansion of our current master´s degrees, certificates, and courses; 2) create a new PhD program in Clinical and Translational Research; 3) create a novel Postdoctoral Translational Scholars Program; 4) consolidate and integrate teaching strategies now used in separate settings; 5) develop translational research tracks in key areas of biomedical and health research, drawing on UM´s areas of strength and spanning the bench-bedside-practice translation loop; 6) enhance access to trained mentors; 7) develop novel alternative learning methodology to increase flexibility and expand the reach of training to a wider segment of the academic, professional, and lay communities; 8) expand the training opportunities to the lay and professional communities in order to facilitate translation from bedside-topractice; 9) expand the pool of under-represented minority scholars by increasing and coordinating recruitment efforts and extending translational research education to undergraduate, predoctoral, and graduate minority students; and 10) continuously evaluate the objectives of translational research training program to determine if objectives are successfully met. This Program will be developed according to MICHR guiding objectives. Because the program is focused on education, the majority of aims align with MICHR Guiding Objective 2 (education and training), but other MICHR guiding objectives are also relevant
Keywords: Achievement; Address; Adopted; Advisory Committees; Area; Basic Science; bench to bedside; Bioinformatics; biomedical informatics; Biometry; career; career development; Clinical; Clinical Research; Clinical Research Curriculum Award; Collaborations; Commit; Communities; Community Health Education; Community Outreach; Complement; Cost Sharing; Data; Dental Students; design; Development; Doctor of Philosophy; Educational Activities; Educational aspects; Educational Curriculum; Educational process of instructing; Educational workshop; Elements; Engineering; Ensure; Equilibrium; Ethics; Event; experience; Exposure to; Faculty; flexibility; Fostering; Funding; Future; Generations; Grant; Health; health disparity; Health Personnel; Home environment; Housing; improved; Individual; innovation; Institutes; Institution; Joints; Laboratories; Leadership; Learning; Master`s Degree; Measurement; Medical Students; meetings; member; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methodology; Methods; Michigan; Minority; Mission; Modeling; National Center for Research Resources; NCI Scholars Program; novel; novel strategies; Nursing Students; Occupations; Outcome; outreach; Patients; Pediatrics; Pharmacy Students; Physician Scientist Award (Program); Physicians; Pilot Projects; Policies; population based; Positioning Attribute; Postdoctoral Fellow; pre-doctoral; Program Effectiveness; programs; Public Health Schools; Qualifying; Recruitment Activity; Research; Research Activity; Research Design; Research Ethics Committees; Research Infrastructure; Research Methodology; Research Personnel; research study; Research Training; Resources; response; Review Committee; Rewards; Science; Scientist; SECTM1 gene; Series; skills; Structure; Students; success; symposium; Technology; Testing; Time; TimeLine; Training; Training and Education; Training Programs; Transcend; Translational Research; Translations; Underrepresented Minority; United States National Institutes of Health; Universities; Work
Project start date: 2007-09-17
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-RM-07-002
5KL2RR024987-05 (2011): $783561
FACULTY DEVELOPMENT PROGRAM FOR PEDIATRIC CLINICIAN-SCIENTISTS
P Thomas
Children´s Memorial Hospital (chicago)city: Chicago country: United States (us)
Grant 5K12HD052902-05 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: A solid grounding in basic research skills is essential for investigators seeking to understand the scientific basis of childhood disease. The long-term goal of this application for a Child Health ResearchCareer Development Award (CHRCDA) is to strengthen the cadre of clinician-scientists at our institution who serve as a critical, bi-directional bridge between the excellent basic research and clinical activities in our academic medical center. We will accomplish this by mentoring and further educating outstanding candidates, helping them become knowledgeable regarding basic science, its relationship to clinical practice, and practical skills important to being physician-scientists such as paper writing, grant preparation and time management. We will accomplish this with a program of mentorship, utilizing successful, experienced investigators who have a track record of nurturing the development of successful investigators. As detailed in the application, our Department has an established track record in preparing physician-scientists for independent research careers. We will offer carefully selected CHRCDA Scholars a closely supervised program that combines protected time, resources and didactic training, along with the mentored research experience. A strong research-intensive environment is described that will offer knowledge, experience and support in facilitating the growth and development of academic pediatricians who will serve as leaders in translational investigation
Keywords: Academic Medical Centers; Award; base; Basic Research; Basic Science; career; Child health care; Childhood; Clinical; clinical practice; Development; Disease; disease/disorder; Disorder; Environment; experience; Faculty; Goals; Grant; Growth and Development; Growth and Development function; Health, Child; Institution; Investigation; Investigators; Knowledge; Mentors; Mentorship; Paper; pediatric; pediatrician; Physicians; Preparation; Program Development; programs; Programs (PT); Programs [Publication Type]; Research; Research Personnel; Research Resources; Researchers; Resources; Scientist; skills; Solid; Time; Time Management; Training; University Medical Centers; Writing
Project start date: 2006-03-01
Project end date: 2011-05-30
Budget start date: 1-DEC-2009
Budget end date: 30-MAY-2011
PFA/PA: RFA-HD-05-027
5K12HD052902-05 (2010): $150175