Cellular Mechanisms in the Pathogenesis of FHC

描述（由申请人提供）： 虽然许多家族性心肌病的遗传基础是 已经确立的病理生理学基础的分子机制 才刚刚开始被描绘出来 家族性肥厚型 心肌病（FHC）是一种原发性心肌疾病， 遗传和临床异质性的显著程度。 迄今为止，所有 与FHC相关的突变编码肌节蛋白。 突变 心肌肌钙蛋白T（cTnT）基因导致特别差的临床结果。 cTnT突变的患者表现出高频率的早期突发性心脏病， 死亡，通常在没有显著的左心室肥大的情况下。 的 心肌肌钙蛋白复合物在调节 收缩装置对肌细胞内条件变化的反应。 一 cTnT突变可能导致收缩功能的改变 并导致不同的肌细胞反应， 心血管生理学的变化。 为了解决这个问题，我们 最近开发了两种独立的转基因小鼠模型， 成人心脏中cTnT相关FHC等位基因 一个突变导致 密码子92处的一个Gln残基被Arg取代（R92Q），而另一个是Gln残基。 剪接位点供体突变，其导致3 '末端的截短， cTnT蛋白（Trunc）。 这两种小鼠模型概括了许多 人FHC的特征，也表明不同的突变， cTnT功能域导致心血管功能的明显变化 在细胞、病理和整个心脏的水平上。 我们的核心假设是 这些等位基因特异性差异是由不适当的激活引起的， 我们将使用这两种动物 模型来充分测试这种可能性。 更好地了解这些 这些过程很可能导致特定的治疗干预， 改变这种疾病的恶性自然史。

DESCRIPTION (provided by applicant): While the genetic basis for many of the familial cardiomyopathies has been well established, the molecular mechanisms that underlie the pathophysiology of these disorders is only beginning to be delineated. Familial Hypertrophic Cardiomyopathy (FHC) is a primary myocardial disorder characterized by a striking degree of both genetic and clinical heterogeneity. To date, all of the mutations linked to FHC encode sarcomeric proteins. Mutations in the cardiac Troponin T (cTnT) gene result in a particularly poor clinical outcome. Patients with cTnT mutations exhibit a high frequency of early sudden cardiac death, often in the absence of significant left ventricular hypertrophy. The cardiac troponin complex plays a central role in modulating the response of the contractile apparatus to changes in intramyocellular conditions. One possibility is that cTnT mutations cause alterations in contractile function and lead to distinct myocellular responses which may result in maladaptive changes in cardiovascular physiology. In order to address this question we have recently developed two independent transgenic mouse models which express cTnT-related FHC alleles in the adult heart. One mutation results in a substitution of a Gin residue for Arg at Codon 92 (R92Q) while the other is a splice-site donor mutation which leads to a truncation of the 3' end of the cTnT protein (Trunc). These two mouse models recapitulate many of the characteristics of human FHC and also demonstrate that mutations in different cTnT functional domains result in distinct changes in cardiovascular function at the cellular, pathologic and whole-heart levels. Our central hypothesis is that these allele-specific differences are caused by inappropriate activation of specific intracellular signaling pathways and we will use these two animal models to fully test this possibility. A better understanding of these processes may well lead to specific therapeutic interventions which could alter the malignant natural history of this disorder.