Initiation of Cardiac Hypertrophy

心脏肥大的开始

基本信息

批准号：
7117240
负责人：
Subha Sen
金额：
$ 37.35万
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

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死亡原因。然而，尚未完全了解心脏病发病机理的基础过程。在跨越几年的调查中，我们在自发性高血压大鼠中鉴定并分析了12 kDa蛋白肌营养素（Myo），可刺激心肌细胞的生长。过去的资金期产生了这些新颖的观察结果：（1）肌过表达会导致心力衰竭变为心力衰竭的心脏肥大，以及相关的细胞因子/生长因子的分子特征在早期疾病与晚期疾病的差异；（2）NFKAPPAB途径的激活对于肌诱导的心脏肥大的进展是必要的；（3）在慢性肥大变成心力衰竭时，会平行出现心肌细胞的细胞分裂和凋亡；（4）Myo的过表达引起了p53的显着强大的过表达，突出了p53在此过程中的可能作用。每个发现将为更多研究提供肥沃的基础，但是我们选择了该更新建议，以关注开关和关闭Myo基因表达的影响，并定义p53在肥厚过程中的作用。我们假设Myo在开始心脏肥大时直接作用于肌细胞，而在过渡到心力衰竭时，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通过（a）使用lettrotol switch评估myo基因的表达或无X层的影响；（b）使用siRNA技术沉默的myo基因；（c）常规对患有心力衰竭的人类进行药理治疗。我们的具体目的是（1）研究通过（a）使用四环素反式激活系统或（b）使用siRNA沉降myo基因的效果；（2）研究单独或组合单个药理剂对肥大程度的影响，随着其发展为心力衰竭，与分子变化有关；（3）定义p53与肥大中肌的关系以及何时发生故障的关系；（4）评估在透射电子显微镜和（5）通过超声心动图确定心脏功能的肥大到心力衰竭期间观察到的结构变化，以将观察到的形态和分子变化相关联。这些发现至关重要的是人类心脏病的治疗。加上对心脏肥大发展为心力衰竭进展的其他分子机制的研究，这些发现将有助于更有效的干预，不仅在有关干预时机的决策中，而且在设计适当的基于分子的疗法方面。