Prevention, treatment, pathogenesis of hypertrophic cardiomyopathy

点击翻译按钮获取中文摘要

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.