Prevention, treatment, pathogenesis of hypertrophic cardiomyopathy

当前SCOR和提议更新的总体目标是阐明心脏肥大和扩张的分子遗传学和生物学，这是心脏对任何形式损伤的两种常见反应。该项目的总体目标是确定关闭突变型肉瘤蛋白的表达或抑制肾素血管紧张素系统（RAS）是否可以预防、减轻或逆转过多的间质胶原、肌细胞紊乱和心功能障碍，并确定介导家族性肥厚性心肌病（FHCM）心脏表型的营养因子。包括心肌肌钙蛋白T （cTnT）在内的肌合成蛋白编码基因突变导致FHCM。FHCM是一种临床表现为心源性猝死（SCD）和心力衰竭的疾病，病理表现为心肌细胞肥大、紊乱和间质胶原过多。目前的研究重点是阐明FHCM的发病机制，并探讨特定干预措施对预防、减弱或逆转表型的影响。为了实现这些目标，我们在转基因小鼠的心脏中表达了已知导致人类FHCM的突变体cTnT-Gln/92蛋白，并建立了一个表现出过度间质胶原、肌细胞紊乱和心功能障碍的模型。心功能障碍先于心肌细胞紊乱和过度间质胶原的发展，这一资助证实了我们在培养心肌细胞中的结果。因此，我们提出FHCM的“原发性”缺陷是心肌细胞收缩能力受损，导致已知[如血管紧张素II (AT)]和新型生长因子的激活，这些生长因子在诱导“继发性”心脏表型（过多的间质胶原，心肌细胞肥大和紊乱）中起着根本作用。为了验证这一假设，我们将确定抑制RAS是否可以预防、减弱或逆转观察到的心脏表型。为了确定FHCM表型的可逆性，我们将建立一个可诱导的转基因小鼠模型，然后关闭突变体cTnT-Gln/92蛋白的表达，并表征间质胶原过多、肌细胞紊乱和心功能障碍的逆转。为了识别新的和新的营养因子，我们将利用DNA微阵列芯片和减法杂交进行表达监测。利用重组腺病毒表征肌细胞的作用，并确定其对胶原合成、肌细胞结构和功能的影响。这些实验的结果有望为FHCM的发病机制提供基本的见解，从而可能导致FHCM的新的治疗或预防方式。

The overall objective of the current SCOR and the proposed renewal is to elucidate the molecular genetics and biology of cardiac hypertrophy and dilatation, two common responses of the heart to any form of injury. The overall objectives of this project are to determine whether switching off expression of the mutant sarcomeric protein or inhibiting the renin angiotensin system (RAS) can prevent, attenuate, or reverse the excessive interstitial collagen, myocyte disarray, and cardiac dysfunction, and to identify the trophic factors that mediate the cardiac phenotype in familial hypertrophic cardiomyopathy (FHCM). Mutations in genes coding for sarcomeric proteins including the cardiac troponin T (cTnT) cause FHCM, a disease characterized clinically by sudden cardiac death (SCD) and heart failure and pathologically by cardiac myocyte hypertrophy, disarray, and excessive interstitial collagen. The research emphasis now is to elucidate the pathogenesis of FHCM, and explore the impact of specific interventions to prevent, attenuate, or reverse the phenotype. In pursuit of these goals, we have expressed the mutant cTnT-Gln/92 protein, known to cause FHCM in man, in the heart of transgenic mouse and developed a model that exhibits excessive interstitial collagen, myocyte disarray, and cardiac dysfunction. Cardiac dysfunction precedes the development of myocyte disarray and excessive interstitial collagen, a funding that confirms our results in cultured cardiac myocytes. Therefore, we proposed that a "primary" defect in FHCM is impaired myocyte contractility leading to activation of known [such as angiotensin II (AT)] and novel growth factors, which play a fundamental role in inducing the "secondary" cardiac phenotypes (excessive interstitial collagen, myocyte hypertrophy, and disarray). To test this hypothesis, we will determine whether inhibiting the RAS can prevent, attenuate, or reverse the observed cardiac phenotype. To determine the reversibility of FHCM phenotype, we will generate an inducible transgenic mouse model and then switch off expression of the mutant cTnT-Gln/92 protein and characterize the reversal of excessive interstitial collagen, myocyte disarray, and cardiac dysfunction. To identify the novel and novel trophic factors, we will perform expression-monitoring utilizing DNA microarray chips and subtraction hybridization. To characterize the role of the myocytes, utilizing recombinant adenoviruses, and determine their impact on collagen synthesis, myocyte structure and function. The results of these experiments are expected to provide fundamental insights into the pathogenesis of FHCM that could lead to new therapeutic or preventive modalities for FHCM.