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Genetic Regulation of Metabolic and Fibrotic Programs in Hypertrophic Heart

肥厚心脏代谢和纤维化程序的基因调控

基本信息

批准号：
8803268
负责人：
M.A.Q Siddiqui
金额：
--
依托单位：
VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8803268
关键词：
Aging Automobile Driving Cardiac Cardiac Myocytes Cardiac Output Categories Cells Cessation of life Cicatrix Collagen Complex DNA Polymerase II Development Disease Event Experimental Models Extracellular Matrix Failure Fibrosis Functional disorder Gene Dosage Gene Expression General Population Genes Genetic Genetic Processes Genetic Programming Genetic Transcription Genomics Goals Heart Heart Diseases Heart Hypertrophy Heart failure Hypertension Hypertrophy Incidence Individual Institute of Medicine (U.S.)Knowledge Laboratories Lead Left Metabolic Metabolic Control Molecular Mus Myocardial Ischemia Myocardium Myofibroblast Nature Outcome Output Pathologic Processes Pathway interactions Phase Physiological Play Positioning Attribute Process Proteins RNA RNA Polymerase II Regimen Regulation Regulator Genes Reporting Research Research Proposals Role STAT3 gene Signal Pathway Signal Transduction Signal Transduction Pathway Staging Stimulus Stress Testing Therapeutic Therapeutic Intervention Transcriptional Activation Transcriptional Elongation Factors Transducers Translating Ventricular Veterans Vietnam War agent orange base biological adaptation to stress effective therapy energy balance extracellular falls gene interaction inhibitor/antagonist innovation insight mouse model preclinical study prevent programs public health relevance response

项目摘要

DESCRIPTION (provided by applicant): The heart responds to stress and increased demand by mounting an adaptive or compensatory hypertrophic response to normalize cardiac output. With prolonged stress, this adaptive phase devolves to a maladaptive or decompensatory hypertrophy marked by the death of metabolically depleted cardiomyocytes and replacement by collagen-producing myofibroblasts that produce a scarring fibrosis. Of the processes underlying the progression to decompensatory hypertrophy, metabolic failure and scarring fibrosis are the most consequential making them key targets for therapeutic intervention. These processes are genetic in nature with well-defined genes and regulatory mechanisms controlling their expression. But exactly how hypertrophic stress signals interact with these regulatory mechanisms to control metabolic or fibrotic gene expression and how this allows the heart to adapt (or not) to stress has yet to be adequately defined. Without this knowledge, attempts to devise therapies to treat cardiac hypertrophy by either maintaining the adaptive or preventing the maladaptive response are likely to be unproductive. The long-term goal of our research is to understand the molecular mechanisms with which the heart translates hypertrophic stress signals into a genomic stress response. Our laboratory has been studying a molecule called CLP-1 (Cardiac Lineage Protein-1) that we have shown to be critical for integrating hypertrophic stress signals into a genomic stress response. CLP-1 is an inhibitory transcriptional modulator that controls the activity of P-TEFb (P-Transcriptional Elongation Factor b), a transcriptional regulator that activates RNA polymerase II to transcribe genes. As a critical regulator of gene transcription, CLP-1 plays an important role in a variety of physiologicl and pathological processes that involve integration of extracellular signals into a coordinated genomic response. The objective of this application is to determine how in response to hypertrophic stimuli CLP-1 controls the transcription of genes in the metabolic program regulating energy substrate usage and in the fibrotic program regulating remodeling of the hypertrophic ventricular myocardium. Our hypothesis is that reduced levels of the CLP-1 transcriptional inhibitor could be increasing the transcriptional competency and responsiveness of compensatory stress response genes, including metabolic genes, in order to maintain cardiomyocyte viability at levels that mitigate formation of the more damaging form of fibrosis, reparative or scarring fibrosis. Our experimental model for examining this hypothesis are mice with reduced CLP-1 gene dosage, CLP-1+/- heterozygous mice, rendered hypertrophic physically or by crossing with established mouse models of hypertrophy. To test our hypothesis, we propose three specific aims. In aim #1, we will determine if the genes directing energy substrate usage are up-regulated to maintain the metabolic output and viability of hypertrophic cardiomyocytes. In aim #2, we will examine the type of fibrosis that develops in CLP-1+/- hypertrophic hearts during the progression from compensatory to decompensatory hypertrophy to determine if reduced CLP-1 levels and sustained metabolic viability of hypertrophic cardiomyocytes mitigates formation of the more severe form of reparative or scarring fibrosis. And in aim #3, we will determine if the CLP-1-P-TEFb regulatory mechanism can directly up-regulate specific stress response genes by potentiating the signal transduction pathway controlling their expression. This approach is innovative in that it shifts the focus away from studies on the causes of heart disease to those focusing on how to prevent the diseased heart from progressing to failure. Since most people with heart disease fall into this latter category, they stand to benefit from the insights our research can provide. In all, our studies should demonstrate that CLP-1 occupies a critical position for controlling the response of cardiac cells to hypertrophic stimuli via its control of stress response genes. These studies are significant since they will provide greater insight into the molecular events underlying the adaptive hypertrophic response and how they can be controlled to mitigate the progression of hypertrophic hearts to contractile dysfunction and failure.

描述（由申请人提供）：