A GENETIC SCREEN FOR HCC GENES
J Adam
University Of Minnesota Twin Citiescity: Minneapolis country: United States (us)
Grant 5R01CA132962-03 from National Cancer Institute
Keywords: A Mouse; Abbreviations; Address; Alcohols; Animal Model; Atlases; base; biomarker; Cancer Etiology; cancer genome; Candidate Disease Gene; chromosome number abnormality; Chronic; Cirrhosis; Clinical Management; comparative genomics; Complex; Computer Simulation; Data; Development; Diagnosis; effective therapy; Family; Fright; Future; gene discovery; Gene Mutation; Gene Transfer; Gene Transfer Techniques; Generations; Genes; Genetic; Genetic Screening; Germ-Line Mutation; Goals; Grant; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocyte; high risk; Human; Human Development; Individual; Insertional Mutagenesis; insight; Inverted Terminal Repeat; Lead; Learning; Liver; Liver Cirrhosis; Liver neoplasms; Loss of Heterozygosity; Malignant Neoplasms; Mediating; Methods; Mission; Modeling; Molecular; mouse model; Murine leukemia virus; Mus; Mutate; Mutation; National Cancer Institute; Neoplasm Metastasis; novel; Oncogenes; outcome forecast; Pathway interactions; Patients; Pattern; Prevalence; Primary carcinoma of the liver cells; Process; public health relevance; Published Database; Recurrence; Role; Sampling; Secondary to; Sleeping Beauty; Somatic Mutation; System; Testing; Translocation Breakpoint; Transposase; tumor; tumor progression; Tumor Suppressor Genes; United States; vector; Virus Diseases; Work
Relevance: This proposal describes work done in mice to understand how certain tumors of the liver, called hepatocellular carcinomas (HCC), develop. We will discover what genes, when damaged, can cause these tumors. This will help us decide how best to treat this dangerous forms of cancer
Project start date: 2009-12-15
Project end date: 2014-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01CA132962-03 (2012): $272628
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to J Adam
EFFECTS OF CHANGES IN MEDICAID PHYSICIAN FEES ON USE OF PREVENTIVE CARE
J Adam, Associate Professor
University Of Colorado Denvercity: Aurora country: United States (us)
Grant 1R21HD071550-01 from Office Of The Director, National Institutes Of Health
Abstract: The purpose of this project is to model the effects of temporary changes in Medicaid physician fees, removal of preventive care copayment rates and Medicaid eligibility expansion in the Patient Protection and Affordable Care Act of 2010 (PPACA) on the use of US Preventive Services Task Force (USPSTF) recommended preventive care among Medicaid enrollees. PPACA appropriates federal dollars to fund increases in physician fees for the Medicaid program to Medicare rates for 2013 and 2014. After 2014, the federal incentive expires and it is up to states to determine if they will continue to fund the payment increase using state funds if Congress does not fund an extension. Traditionally, each state has set its own Medicaid reimbursement rates and has had wide discretion in eligibility rules and copayment structure. Federal Medicaid law does not define preventive services, include these services under a mandatory benefit category or track specific preventive services covered for adults by each Medicaid program. This has led to substantial geographic variation in Medicaid plan design and use of preventive services, with not all USPSTF services covered in all states and substantial differences in provider reimbursement and beneficiary cost sharing. This study will examine the effect of the previous increases in physician fees on the use of USPSTF recommended preventive care services and model the projected impact of additional utilization increases under PPACA. Similarly, we will estimate the effects of the elimination of this financial incentive after 2014. We will also estimate the cost of increases in the use of these preventive services, resulting from the increase in physician fees, the removal of copayments, and the eligibility expansion to parents and childless adults. To answer these questions, we will use data from the Medical Expenditure Panel Survey (MEPS) and the National Ambulatory Medical Care Survey (NAMCS). The project will answer an important research question that will be critical for the next step in health reform. When the federal subsidies for higher Medicaid reimbursement and program expansions expire in 2014, states will make choices about which elements to retain and which to discard. It will be critical that there be scientific evidence regarding the impact of the different policy options. Currently, that evidence is lacking. This study will provide guidance to states about the likely effect of different policy choices on the use of preventive care in low income populations. This study will provide guidance to states about the likely effect of different policy choices embedded in the Patient Protection and Affordable Care Act of 2010 on the cost and use of preventive care in low income populations
Keywords: Adult; Advisory Committees; beneficiary; Caring; Categories; Congresses; copayment; cost; Cost Sharing; Data; design; Elements; Eligibility Determination; Excision; Expenditure; Fees; financial incentive; Funding; Future; geographic difference; Health; Incentives; Insurance; Laws; Low Income Population; Medicaid; Medical; Medical Assistance; Medicare; Modeling; Monitor; National Ambulatory Medical Care Survey; Parents; Patients; payment; Physicians; Policies; Population; Preventive; Primary Care Physician; Primary Health Care; programs; Provider; Research; safety net; Services; Structure; Surveys; Techniques; trend; United States Centers for Medicare and Medicaid Services; Variant
Relevance: This study will provide guidance to states about the likely effect of different policy choices embedded in the Patient Protection and Affordable Care Act of 2010 on the cost and use of preventive care in low income populations
Project start date: 2011-09-24
Project end date: 2013-06-30
Budget start date: 24-SEP-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-RM-10-015
1R21HD071550-01 (2011): $199656
MECHANISMS OF EFFECTOR CD4 CELL TOLERIZATION
J Adam, Assoc Prof. Of Medicine
University Of Connecticut Sch Of Med/dntcity: Farmington country: United States (us)
Grant 2R56AI057441-06 from National Institute Of Allergy And Infectious Diseases
Abstract: The immune system utilizes a variety of tolerance mechanisms to prevent autoreactive T cells from becoming activated. The majority of self-reactive specificities are eliminated through negative selection during thymic development, however, a significant fraction reach maturity and migrate to peripheral lymphoid organs where they must be controlled by peripheral tolerance mechanisms. Using a TCR transgenic adoptive transfer system we previously found that naive CD4 cells specific for a ¿generic¿ parenchymal self-antigen are rendered non-responsive/anergic by bone marrow-derived antigen presenting cells (APC) that acquire and indirectly present cognate parenchymal self-antigen. Additionally, CD4 cells that are initially primed through viral infection to differentiate into Th1 effectors are also susceptible to undergoing inactivation following exposure to APC presenting cognate self-antigen, and during this tolerization process the ability to express the effector cytokines IFN-? and TNF-a are lost more rapidly than the ability to express IL-2 and to proliferate. This preferential loss of IFN-? and TNF-a expression potential during CD4 cell tolerization likely has physiological and clinical relevance since these effector cytokines can facilitate both tumor immunity and autoimmunity, and thus understanding the underlying mechanisms has been a major focus of this project. During the current funding cycle we have found that dendritic cells present parenchymal self-antigen and vaccinia-viral antigen to induce cognate naive and Th1 effector CD4 cells to undergo tolerization and priming, respectively, although at least one other bone marrow-derived APC population can also perform these functions. In characterizing CD4 cellintrinsic mechanisms of tolerization, we have found that at least three separate lesions negatively impact cytokine expression. The first is a TCR-proximal signaling blockage that impacts expression of IL-2, IFN- ? and TNF-a. Additionally, IFN-? expression is selectively impaired through modulation of the expression level of the transcription factor T-bet as well as the extent of chromatin remodeling that occurs within the Ifng gene locus, while TNF-a expression is selectively diminished through translational repression of TNF-a mRNA. In this competitive renewal application we propose to continue studying both CD4 cellextrinsic and ¿intrinsic mechanisms that underlie the peripheral tolerization of both naive and Th1 effector CD4 cells
Keywords: Adoptive Transfer; Antigen-Presenting Cells; Autoantigens; Autoimmune Diseases; Autoimmunity; autoreactive T cell; Bone Marrow; CD4 Positive T Lymphocytes; chromatin remodeling; clinically relevant; cytokine; Cytokine Gene; Dendritic Cells; Development; Distal; Elements; Etiology; Exposure to; Funding; Generic Drugs; Genes; human DICER1 protein; Immune system; insight; Interferons; Interleukin-2; Lesion; Link; Lymphoid; Mediating; Messenger RNA; mRNA Stability; Organ; Peripheral; Physiological; Population; Post-Transcriptional Regulation; prevent; Process; Proliferating; Signal Transduction; Specificity; System; T-bet protein; T-Lymphocyte; Therapeutic; Transgenic Organisms; Translational Repression; Tumor Immunity; Vaccinia; Viral Antigens; Virus Diseases
Relevance: Self-reactive T cells are normally prevented from mediating autoimmunity through a variety of central and peripheral tolerance mechanisms. This project will study the mechanisms that regulate peripheral tolerance for CD4+ T cells, and will thus provide insight into understanding the etiology of autoimmune diseases as well as potential therapeutic avenues for managing autoimmunity
Project start date: 2003-12-01
Project end date: 2011-08-30
Budget start date: 28-SEP-2009
Budget end date: 30-AUG-2011
PFA/PA: PA-07-070
2R56AI057441-06 (2009): $382500
MECHANISMS OF APOPTOSIS INHIBITION IN MATURING NEURONS: FOCUS ON MIR-29 AND DICER
J Adam, Graduate Student Research Assistant
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 5F30NS068006-02 from National Institute Of Neurological Disorders And Stroke
Abstract: Post-mitotic cells such as neurons must strictly regulate the pathway of apoptosis because these cells have limited regenerative potential and must survive for the lifetime of the organism. Understanding the molecular mechanisms of apoptosis, or programmed cell death, in neurons has enormous clinical significance due to the wide range of diseases which result from aberrant apoptotic regulation. For example, excessive activation of neuronal apoptosis is seen in neurodegenerative diseases and after stroke. On the other hand, evasion of cell death is a hallmark of cancer. In order to understand the pathogenesis of these diseases and to develop new therapeutics, it is crucial that we understand the molecular mechanisms of how neurons choose to live or die. The long-term objectives of this project are to further the understanding of changes that occur in the regulation of apoptosis in the maturing sympathetic nervous system. Consistent with their need for long-term survival, we find that sympathetic neurons utilize an increasing number of mechanisms to prevent unwanted activation of the apoptotic pathway as they mature. Using microarrays, I have identified changes in microRNA (miRNA) expression that correlate with changes in apoptotic restriction as sympathetic neurons mature. I hypothesize that these changes in miRNA expression have an important role in regulating the ability of these cells to survive cellular stresses. The specific aims of this proposal are two-fold 1) to determine how one miRNA, which is upregulated during neuronal maturation, is able to protect neurons from apoptotic stimuli, and 2) to determine if downregulation of the miRNA biogenesis machinery has a role in protecting mature neurons from apoptosis. Neurons inappropriately die in many neurological diseases, leading to subsequent disability or death of patients. The experiments proposed in this grant will help explain how neurons are normally able to survive for an organism´s lifetime and may shed light on how this process malfunctions when cells die. This information could lead to new therapies for preventing unwanted neuronal death seen in neurodegenerative disease or as a result of stroke
Keywords: Apoptosis; Apoptotic; Biogenesis; Cell Death; Cells; Cellular Stress; Cessation of life; clinically significant; disability; Disease; Down-Regulation; Grant; human DICER1 protein; Inhibition of Apoptosis; Lead; Life; Light; Malignant Neoplasms; MicroRNAs; Mitotic; Molecular; nervous system disorder; Neurodegenerative Disorders; neuron apoptosis; Neurons; novel therapeutics; Organism; Pathogenesis; Pathway interactions; Patients; prevent; Process; public health relevance; regenerative; Regulation; research study; Role; Stimulus; stroke; Sympathetic Nervous System
Relevance: Neurons inappropriately die in many neurological diseases, leading to subsequent disability or death of patients. The experiments proposed in this grant will help explain how neurons are normally able to survive for an organism´s lifetime and may shed light on how this process malfunctions when cells die. This information could lead to new therapies for preventing unwanted neuronal death seen in neurodegenerative disease or as a result of stroke
Project start date: 2010-07-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-09-207
5F30NS068006-02 (2011): $34304
TOWARDS SMALL MOLECULE MODULATORS OF RGS PROTEINS
J Adam
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 5F30MH074266-05 from National Institute Of Mental Health
Abstract: Neurotransmitter signaling often involves activation of G protein-coupled receptors (GPCRs). Modulation of neurotransmitter receptor signaling is a key therapeutic tool in ameliorating the cognitive pathologies of diseases such as schizophrenia and depression. "Regulator of G-protein signaling" (RGS) proteins are key components of GPCR signaling that act as GTPase-accelerating proteins or "GAPs" for Ga subunits, dramatically increasing their intrinsic GTP hydrolysis activity. In order to advance the utility of RGS proteins as drug discovery targets for cognitive pathologies, the specific aims of this research proposal are to delineate the structural determinants of allosteric modulation of RGS-box GAP activity and to identify small molecule inhibitors and activators of RGS-box GAP activity by computational approaches. Statistical coupling analyses of RGS-box sequences and site identification algorithms applied to known RGS-box structures will guide in silico docking of compounds from commercial and public compound libraries. The activity of compound "hits" identified in these screens will be evaluated using fluorescence- and surface plasmon resonance-based in vitro assays of RGS-box Ga-binding and Ga-GAP activities. Verified modulators of RGS-box GAP activity will then be evaluated in cellular assays of receptor/G-protein/effector function, including receptor-dependent activation of heterotrimer steady-state GTPase activity and of phospholipase C activity. These pursuits should identify proof-of-principle small molecule modulators of RGS protein action that will establish RGS proteins as valid targets for therapeutic intervention in future pharmacotherapy of CNS disorders
Keywords: Algorithms; base; Binding (Molecular Function); Boxing; Calmodulin; Cellular Assay; Central Nervous System Diseases; Clinical; Cognitive; Computer Simulation; Coupled; Coupling; Development; Disease; Docking; drug discovery; Drug effect disorder; Fluorescence; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein Regulators; GTP-Binding Proteins; guanine nucleotide binding protein; Guanosine; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Heterotrimeric GTP-Binding Proteins; Hydrolysis; in vitro Assay; inhibitor/antagonist; Laboratories; Libraries; member; Mental Depression; Molecular; Neurons; Neurotransmitter Receptor; Neurotransmitters; Pathology; Pathway interactions; Pharmacotherapy; Phospholipase C; Phospholipids; Play; Proteins; receptor; Receptor Signaling; Research Proposals; RGS Proteins; Role; Schizophrenia; Signal Transduction; Site; Site-Directed Mutagenesis; small molecule; Structure; success; Surface Plasmon Resonance; Testing; Therapeutic; Therapeutic Intervention; therapeutic target; tool
Project start date: 2007-03-31
Project end date: 2012-03-30
Budget start date: 31-MAR-2011
Budget end date: 30-MAR-2012
PFA/PA: PA-99-089
5F30MH074266-05 (2011): $32474
IDENTIFYING GENETIC MECHANISMS IN T-ALL WITH AN INDUCIBLE SLEEPING BEAUTY SYSTEM
J Adam, Assistant Professor
University Of Iowacity: Iowa City country: United States (us)
Grant 5R01CA130867-04 from National Cancer Institute
Abstract: Nearly four thousand cases of acute lymphoblastic leukemia (ALL) occur each year in this country. The majority of these develop in children under the age of 19 making it the most common form of childhood cancer. Fortunately, with an 80% survival rate, ALL is also among the most treatable forms of cancer. However, childhood cancer survivors face long-term health complications as the result of treatment. New treatments are required that do not decrease the quality of life of cancer patients long-term. Most likely these treatments will involve the use of targeted cancer therapeutics as this approach has had recent success. The development of targeted therapeutics necessarily requires an understanding of the molecular mechanisms that contribute to cancer. A recent study identified activating mutations in NOTCH1 in more than 50% of T-lineage ALL patients suggesting that NOTCH1 may be a valid therapeutic target. Given the importance of this pathway in T-ALL additional studies to understand the genetic mechanisms that synergize with NOTCH1 would be beneficial in designing more effective treatments. It has been proposed that the prevalence of NOTCH1 mutations in T-ALL is due to the role of the Notch pathway in the regulation of hematopoietic stem cells. Little is known about the genetic mechanisms that act differentially to transform stem cells and committed progenitor cells. This is mainly due to the inability to determine the biological state of the cell that initiates a tumor. Our recent work has produced a Sleeping Beauty (SB) transposon system that can be used to perform forward genetic screens in mice to identify cancer genes. We propose a series of experiments using a Cre-inducible SB system to address two fundamental questions in the genetics of T-ALL. The fist aim seeks to identify mutations that accelerate lymphomas induced by constitutive Notch signaling. The second aim will utilize the Cre- inducible SB transposon system to induce lymphomas by mutagenizing hematopoietic stem cells or committed T-cell progenitors. In both cases mutations found in tumors will be tagged by transposons allowing us to rapidly identify the genes involved in each process. Genes that are mutated in SB-induced lymphomas can quickly be evaluated for a potential role in human cancer. Nearly four thousand cases of acute lymphoblastic leukemia (ALL) occur each year in this country. The majority of these develop in children under the age of 19 making it the most common form of childhood cancer. Activating mutations in NOTCH1 are found in more than 50% of T-lineage ALL patients. Given the importance of this pathway in T-ALL additional studies to understand the genetic mechanisms that synergize with NOTCH1 would be beneficial in designing more effective treatments
Keywords: Acute T Cell Leukemia; Address; Affect; Age; Biological; Bone Marrow; Cancer Patient; CD8B1 gene; Cell Culture Techniques; Cell Lineage; Cells; cellular targeting; Child; childhood cancer survivor; Commit; Country; design; Development; effective therapy; Event; Face; Family; Genes; Genetic; Genetic Screening; Goals; Health; Hematopoiesis; Hematopoietic stem cells; Human; insight; Interleukin-2; Lead; Leukemia, Lymphocytic, Acute; Lymphoid Cell; Lymphoma; Malignant Childhood Neoplasm; Malignant Neoplasms; Modeling; Molecular; mouse model; Mus; Mutagenesis; mutant; Mutate; Mutation; notch protein; NOTCH1 gene; novel; novel therapeutic intervention; Oncogenes; Pathway interactions; Patients; Point Mutation; Prevalence; Process; progenitor; Quality of life; Regulation; research study; Role; Series; Signal Transduction; Sleeping Beauty; Staging; Stem cells; success; Survival Rate; Survivors; System; T cell differentiation; T-Cell Lymphoma; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; therapeutic target; thymocyte; Time; Transgenes; tumor; Validation; Work
Project start date: 2008-09-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01CA130867-04 (2011): $301913
PRENATAL LOW LEVEL TOBACCO & PHTHALATE EXPOSURE & CHILDHOOD RESPIRATORY HEALTH
J Adam
Pennsylvania State Univ Hershey Med Ctrcity: Hershey country: United States (us)
Grant 5K23ES016304-04 from National Institute Of Environmental Health Sciences
Abstract: Asthma and respiratory infection pose major burdens to child health. Prenatal tobacco exposure is a key risk factor for wheeze in young children, but there is little data about the relationship of prenatal low level exposures to tobacco (e.g. passive exposure of nonsmoking pregnant women) with risk of childhood wheeze or respiratory infection. There is emerging, yet limited evidence for novel environmental risk factors for wheeze such as phthalates. Advances in biomarkers offer an ability to quantify indicators of internal dose directly, reduce exposure misclassification, and enhance our ability to link exposures with disease. The primary objective for this K23 proposal is to rigorously characterize the relationship of common environmental exposures with risk of wheeze and respiratory infection in early childhood using serial biomarkers of exposure. The specific aims are to 1) Test which measure of prenatal tobacco smoke exposure (different biomarkers, parent-report) is most strongly associated with risk of wheeze, respiratory infection, and pulmonary inflammation (fraction of exhaled nitric oxide, FeNO) in the first three years of life; 2) Investigate the association of low levels of maternal passive tobacco smoke exposure during pregnancy with risk of wheeze, respiratory infection, and pulmonary inflammation (FeNO) in children of nonsmoking mothers in the first three years of life; and 3) Investigate the association of prenatal phthalate exposure with risk of wheeze, respiratory infection, and pulmonary inflammation in the first three years of life. This proposal is novel because it uses serial biomarkers to measure individual exposure burden and low levels of exposure objectively throughout pregnancy and early childhood. Additionally, we will be the first to explore the role of prenatal phthalate exposure with the risk of childhood wheeze, respiratory infection, and pulmonary inflammation using biomarkers. Through this K23, will develop expertise in pediatric environmental epidemiology to position him to help broaden the model of environmental toxicology and respiratory epidemiology in children. It will also provide the background and training needed to develop an independent research career in clinical pediatrics and enhance our understanding of how environmental risk factors affect the development and exacerbation of pediatric asthma and respiratory disease and integrate this knowledge into prevention and treatment efforts
Keywords: Accounting; Affect; Allergic; Asthma; base; biomarker; Birth; career; Case-Control Studies; Child; Child health care; Childhood; Childhood Asthma; Clinic Visits; Clinical; cohort; Cosmetics; Cotinine; cytokine; Data; Development; Disease; Dose; Dust; early childhood; Enrollment; Environment; Environmental Epidemiology; Environmental Exposure; Environmental Health; Environmental Risk Factor; environmental toxicology; Epidemiology; Evaluation; Exhalation; Exposure to; Female of child bearing age; fetal tobacco exposure; Fetus; Food Packaging; Funding; Growth and Development function; Hair; Health; Human Cell Line; IL8 gene; improved; Individual; Infant; Infant Behavior; Interleukin-6; K-Series Research Career Programs; Knowledge; Lead; Life; Link; Lung diseases; maternal serum; Measures; Meconium; Medical; Mentors; Modeling; Molecular Epidemiology; Morbidity - disease rate; Mothers; Newborn Infant; Nicotine; Nitric Oxide; novel; Outcome; Outcome Measure; Parents; Participant; patient oriented; Patient Self-Report; Pediatrics; Perinatal; phthalates; Plastics; Pneumonia; Positioning Attribute; postnatal; Pregnancy; Pregnant Women; prenatal; prenatal exposure; Prevalence; Prevention; pulmonary function; rapid growth; Relative (related person); Reporting; Research; Research Infrastructure; Research Personnel; respiratory; Respiratory Tract Infections; Risk; Risk Factors; Role; Second Pregnancy Trimester; Serum; Smoke; Smoking; smoking prevalence; Source; Surveys; Symptoms; Techniques; Testing; Tobacco; Tobacco smoke; Toxic Environmental Substances; Toy; Training; United States National Institutes of Health; Urine; Wheezing
Project start date: 2008-07-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-05-143
5K23ES016304-04 (2011): $177637
CARDIOLIPIN AND LINOLEATE METABOLISM IN THE FAILING HEART: EFFECTS ON MITOCHONDRI
J Adam, Assistant Professor
Colorado State University-fort Collinscity: Fort Collins country: United States (us)
Grant 5R21HL094890-02 from National Heart, Lung, And Blood Institute
Abstract: Accumulating evidence indicates that mitochondrial dysfunction contributes to the pathogenesis and/or progression of heart failure by reducing the capacity and/or efficiency of myocardial respiration and increasing production of reactive oxygen species. However, the development of efficacious therapies targeting these perturbations has been limited by an incomplete understanding of their molecular basis. Studies by our laboratory and others indicate that alterations in the metabolism of polyunsaturated fatty acids (PUFAs) may play an important role in these phenomena during development of heart failure by leading to dramatic changes in the fatty acid composition of myocardial phospholipids, particularly cardiolipin (CL) a unique tetra-acyl mitochondrial phospholipid that provides essential support to proteins involved in mitochondrial respiration. CL is optimally functional in the mammalian heart when it contains four linoleic acid (182) acyl chains (1824CL), a conformation generated by a molecular remodeling process requiring 182 as a substrate. Decreases in myocardial 1824CL have been reported in several cardiac pathologies associated with mitochondrial dysfunction, including human dilated cardiomyopathy, and multiple rodent models of heart failure and diabetic cardiomyopathy. Interestingly, in all of these pathologies, decreases in 1824CL can be accounted for largely by dramatic increases in CL species containing highly unsaturated fatty acid (HUFAs, chiefly, arachidonic acid (204) and/or DHA (226)), which parallel a global loss of 182 and accumulation of these HUFAs in the global myocardial phospholipid fatty acid pool. Recent studies in our laboratory indicate that this remodeling of myocardial phospholipids results from increased expression/activity of delta-6 desaturase (D6D) the rate- limiting enzyme in the biosynthesis of HUFAs from 182 and linolenic acid (183). Pharmacological inhibition of D6D in spontaneously hypertensive heart failure (SHHF) rats and obese/insulin resistant (ob) mice normalized the CL compositional profile, improved mitochondrial respiratory function, reduced mitochondrial ROS production, and decreased lipoxidative stress to levels near their respective healthy controls. The studies in this proposal will determine if upregulation D6D is sufficient to elicit the mitochondrial dysfunction and cardiac pathology with which it has been associated in these studies, and the extent to which cardiomyocyte D6D (as opposed to liver or "systemic" D6D activity) contributes to the desaturation of CL and membrane fatty acids in the failing heart. We will accomplish these aims by 1) examining the uptake and desaturation of 2H-labeled PUFAs into CL and other phospholipid species of cardiomyocytes isolated from failing and non-failing SHHF rats in the presence and absence of pharmacological or siRNA-mediated inhibition of D6D, and 2) by characterizing the cardiac mitochondrial phenotype of a transgenic mouse with global overexpression of D6D. These studies will shed new light on the mechanism and pathophysiological significance of a widely reported phenomenon that may contribute to the pathogenesis of several prevalent forms of myocardial disease. Recent studies in our laboratory indicate that changes in the composition of fatty acids in the heart leads to pathologic changes in cardiac mitochondria, the ´powerhouses´ of heart cells, that may contribute to the development and/or progression of heart failure. The studies in this proposal will elucidate the mechanisms and pathological importance of these phenomena in hopes of developing new therapeutic strategies for the management of heart disease
Keywords: Accounting; Aging; Anabolism; Arachidonic Acids; base; Cardiac; Cardiac Myocytes; Cardiolipins; Cardiomyopathies; Cardiovascular Diseases; Development; diabetic cardiomyopathy; Dilated Cardiomyopathy; Enzymes; Fatty Acids; Heart; heart cell; Heart Diseases; Heart failure; Heart Research; Human; Hypertrophy; improved; Insulin Resistance; Label; Laboratories; Light; Link; Linoleic Acids; Linolenic Acids; linoleoyl-CoA desaturase; Liver; Mediating; Membrane; Metabolism; Mitochondria; mitochondrial dysfunction; Molecular; Molecular Conformation; Mus; Myocardial; novel therapeutics; Obesity; overexpression; Pathogenesis; Pathologic; Pathology; Phenotype; Phospholipids; Play; Polyunsaturated Fatty Acids; pressure; Process; Production; Proteins; public health relevance; Rattus; Reactive Oxygen Species; Reporting; Research; Respiration; Respiratory physiology; Rodent Model; Role; Small Interfering RNA; Stress; Transgenic Mice; Unsaturated Fatty Acids; Up-Regulation (Physiology); uptake; Ventricular Remodeling; Work
Relevance: Recent studies in our laboratory indicate that changes in the composition of fatty acids in the heart leads to pathologic changes in cardiac mitochondria, the ´powerhouses´ of heart cells, that may contribute to the development and/or progression of heart failure. The studies in this proposal will elucidate the mechanisms and pathological importance of these phenomena in hopes of developing new therapeutic strategies for the management of heart disease
Project start date: 2010-04-15
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-09-164
5R21HL094890-02 (2011): $180976
1R21HL094890-01A1 (2010): $217858