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 已经确定的，病理生理学基础的分子机制 这些疾病中的一种才刚刚开始被描述出来。家族性肥厚 心肌病(FHC)是一种原发性心肌疾病，其特征是 显著程度的遗传和临床异质性。迄今为止，所有的 与FHC相关的突变编码肌瘤蛋白。基因突变 心肌肌钙蛋白T(CTnT)基因导致的临床结果特别差。 CTnT突变的患者早期心脏骤停的频率很高 死亡，通常在没有明显左室肥厚的情况下。这个 心肌肌钙蛋白复合体在调节血管紧张素转换酶的反应中起核心作用。 对心肌细胞内状态变化的收缩装置。一 可能是cTnT突变导致收缩功能改变 并导致不同的肌细胞反应，这可能导致适应不良 心血管生理学的变化。为了解决这个问题，我们 最近开发了两个独立的转基因小鼠模型，它们表达了 成人心脏cTnT相关FHC等位基因的研究一种突变会导致 在密码子92(R92Q)上用Gin残基取代Arg，而另一个是 剪接位点供体突变导致基因3‘端截断 CTnT蛋白(Trunc)。这两个小鼠模型概括了许多 人类FHC的特征，也表明不同基因的突变 CTnT功能域导致心血管功能的明显变化 在细胞、病理和全心脏水平上。我们的中心假设是 这些等位基因特异性差异是由不适当的激活引起的 特定的细胞内信号通路，我们将用这两种动物 模型来充分测试这一可能性。更好地理解这些 这一过程很可能导致特定的治疗干预，这可能 改变这种疾病的恶性自然病史。

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.