Initiation of Cardiac Hypertrophy

心脏肥大的开始

基本信息

批准号：
7254909
负责人：
Subha Sen
金额：
$ 36.27万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-12-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7254909
关键词：
Age Apoptosis Atrial Natriuretic Factor Cardiac Cardiac Myocytes Cause of Death Cell division Chronic Chronic Phase Connexins DNA Microarray Chip DNA Microarray format Data Disease Disease Progression Drug usage Echocardiography Electron Microscope FOS gene Failure Funding Gene Chips Gene Expression Genes Genetic Transcription Growth Growth Factor Heart Heart Diseases Heart Hypertrophy Heart failure High Blood Pressure Human Hypertension Hypertrophy Inbred SHR Rats Individual Intervention Investigation Laboratories Measures Mechanics Modeling Molecular Molecular Profiling Mus Muscle Cells Myocardial Myocardium Myosin Heavy Chains Pathogenesis Pathway interactions Pharmacological Treatment Phase Play Process Protein Biosynthesis Protein Overexpression Proteins Purpose RNA Interference Research Personnel Role Small Interfering RNA Staging Stress System TP53 gene Techniques Technology Testing Tetanus Helper Peptide Tetracycline Tetracyclines Therapeutic Time Transactivation Transgenic Organisms Transmission Electron Microscopy United States Up-Regulation Ursidae Family Week Work base c-myc Proto-Oncogenes cell growth cytokine design interdisciplinary approach mouse model multidisciplinary myotrophin novel prevent programs release factor transmission process

项目摘要

DESCRIPTION (provided by applicant): Cardiac hypertrophy and heart failure are leading causes of death in the United States. However, the molecular processes underlying the pathogenesis of heart disease have not been thoroughly understood. During investigations spanning several years we identified and profiled in spontaneously hypertensive rats a 12-kDa protein, myotrophin (Myo), that stimulates myocyte growth. The past funding period has yielded these novel observations: (1) Myo overexpression causes cardiac hypertrophy that devolves to heart failure, and the molecular profiles of associated cytokines/growth factors differ in early- vs. late-stage disease; (2) activation of the NFkappaB pathway is necessary for the progression of Myo-induced cardiac hypertrophy; (3) at the point when chronic hypertrophy becomes heart failure, cell division and apoptosis of cardiac myocytes occur in parallel; and (4) Myo overexpression elicits significant, robust overexpression of p53, highlighting a possible role of p53 in this process. Each finding would provide fertile ground for more investigation, but we chose in this renewal proposal to focus on the effects of turning Myo gene expression on and off and defining the role of p53 in the hypertrophic process. We hypothesize that Myo acts directly on myocyte during initiation of cardiac hypertrophy, whereas it acts in synergy with p53 and other cytokines/growth factors at the point of transition to heart failure. To test this hypothesis, we propose a multidisciplinary approach to evaluating the effects of the expression or nonexpression of the Myo gene by (a) using a let-control switch; (b) silencing the Myo gene using siRNA technology; or (c) administering pharmacological treatment conventionally given to humans with heart failure. Our specific aims are (1) to study the effects of altering Myo gene expression by either (a) using a tetracycline transactivation system or (b) silencing the Myo gene using siRNA; (2) to study the effects of individual pharmacologic agents, alone or in combination, on the degree of hypertrophy as it progresses to heart failure, associated with molecular changes; (3) to define what relationship p53 has to Myo in hypertrophy and when it worsens to failure; (4) to evaluate structural changes observed during initiation/progression of hypertrophy to heart failure by transmission electron microscopy and (5) to determine cardiac function by echocardiogram to correlate observed morphological and molecular changes. These findings bear crucially upon the treatment of heart disease in humans. Together with investigations into additional molecular mechanisms that underlie the progression of cardiac hypertrophy to heart failure, the findings will facilitate more effective intervention, not only in decisions regarding the timing of intervention, but also in the design of appropriate molecularly based therapies.

描述（由申请人提供）：心脏肥大和心力衰竭是美国的主要原因。然而，心脏病发病机制的分子过程尚未完全了解。在长达数年的研究中，我们在自发性高血压大鼠中发现并分析了一种 12 kDa 的肌营养蛋白 (Myo)，它可以刺激肌细胞生长。过去的资助期产生了这些新的观察结果：（1）Myo 过度表达导致心脏肥大，进而发展为心力衰竭，并且相关细胞因子/生长因子的分子特征在早期与晚期疾病中有所不同； (2) NFκB通路的激活对于Myo诱导的心脏肥大的进展是必要的； (3)当慢性肥厚发展为心力衰竭时，心肌细胞的细胞分裂和凋亡同时发生； (4) Myo 过度表达引起 p53 显着、稳健的过度表达，突出了 p53 在此过程中可能发挥的作用。每项发现都将为更多研究提供沃土，但我们在这个更新提案中选择将重点放在打开和关闭 Myo 基因表达的影响以及定义 p53 在肥大过程中的作用。我们假设，Myo 在心脏肥大开始时直接作用于心肌细胞，而在向心力衰竭转变时，它与 p53 和其他细胞因子/生长因子协同作用。为了检验这一假设，我们提出了一种多学科方法来评估 Myo 基因表达或不表达的影响，方法是：（a）使用 let-control 开关； (b)使用siRNA技术沉默Myo基因； (c) 给予心力衰竭患者常规的药物治疗。我们的具体目标是 (1) 研究通过 (a) 使用四环素反式激活系统或 (b) 使用 siRNA 沉默 Myo 基因来改变 Myo 基因表达的效果； (2) 研究单独或联合使用的单个药物对肥厚程度的影响，当肥厚进展为心力衰竭时，与分子变化相关； (3) 定义 p53 与 Myo 肥大以及何时恶化至衰竭的关系； (4)通过透射电子显微镜评估在肥厚开始/进展为心力衰竭期间观察到的结构变化，以及(5)通过超声心动图确定心脏功能以关联观察到的形态和分子变化。这些发现对于人类心脏病的治疗至关重要。结合对心脏肥大进展为心力衰竭的其他分子机制的研究，这些发现将有助于更有效的干预，不仅在干预时间的决策上，而且在适当的分子疗法的设计上。