FHC Tn Mutations: Functional Consequences & Mechanisms

家族性肥厚性心肌病（FHC）是一种常染色体显性遗传病，它与几乎所有主要心肌组织蛋白的突变有关。一般来说，肌球蛋白重链（MHC）突变的个体心肌肥厚程度较高，而心肌肌钙蛋白T （CTnT）和一些已报道的肌钙蛋白I （CTnI）突变的个体心肌肥厚程度较低，心源性猝死（SCD）的发生率较高。最近，有报道称肌钙蛋白C的单一突变可能与FHC有关。尽管一些突变在体外已被广泛表征，但尚不清楚它们是如何引起心脏肥厚或SCD的。我们的工作假设是FHC肌钙蛋白突变改变了ca -力和- atp酶的关系，肌肉发展最大力量和atp酶活性的能力，肌球蛋白过桥动力学，收缩效率和肌肉工作的能力。这种增加Ca2+敏感性的突变与猝死的关系更密切，而那些降低肌肉发展力量能力的突变与肥大的关系更密切。最近报道的转基因小鼠结果以及我们对表达人类CTnT (HCTnT) FHC突变（I79N， F1101和R278C）和HCTnI-R145G的三个转基因小鼠系的数据支持了这一假设。本课题的目的是综合研究现有和新型转基因小鼠中不同FHC相关肌钙蛋白突变的体外影响（如Ca2+收缩敏感性、力发展/松弛动力学、CTnI抑制功能受损等），以确定FHC发病的关键机制。该应用程序汇集了迈阿密大学具有不同背景的才华横溢的科学家，代表了研究这些肌钙蛋白突变的综合方法。我们的目标是将动物模型中观察到的CTnT、CTnI和CTnC突变对Ca2+调控心肌收缩的影响与人类FHC的发病机制联系起来，特别是在已经报道过心源性猝死的病例中。这些研究将确定在相同实验条件下不同肌钙蛋白T、肌钙蛋白I和肌钙蛋白C突变的功能后果，从而有助于确定肌钙蛋白相关FHC发病机制的关键机制，并导致潜在的治疗策略

Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disease, which has been associated with mutations in almost every major cardiac sarcomeric protein. Whereas individuals with myosin heavy chain (MHC) mutations, in general, have a higher level of cardiac hypertrophy, those with cardiac Troponin T (CTnT) and some of the reported Troponin I (CTnI) mutations have less hypertrophy and a higher incidence of sudden cardiac death (SCD). Most recently, a single mutation in Troponin C has been reported to be possibly associated with FHC. Although several mutations have been extensively characterized in vitro, it is still unclear how they cause cardiac hypertrophy or SCD. Our working hypothesis is that FHC troponin mutations alter the pCa-force and -ATPase relationships, the ability of the muscle to develop maximum force and ATPase activity, myosin cross-bridge kinetics, efficiency of contraction, and the ability of the muscle to do work. That mutations, which increase Ca2+- sensitivity, are more closely associated with sudden death, while mutations, which decrease the ability of the muscle to develop force, are more closely associated with hypertrophy. Recently reported transgenic mouse results along with our data from three transgenic mouse lines expressing the human CTnT (HCTnT) FHC mutations (I79N, F1101 and R278C) and HCTnI-R145G, support this hypothesis. The objective of this proposal is to comprehensively study the in vitro consequences (e.g. Ca2+-sensitivity of contraction, kinetics of force development/relaxation, impaired CTnI inhibitory function, etc.) of different FHC associated Troponin mutations in existing and new transgenic mice to identify the key mechanisms involved in the pathogenesis of FHC. This application brings together highly talented scientists at the University of Miami with varied backgrounds and represents a comprehensive approach to the study of these troponin mutations. Our goal is to correlate, the observed effects of mutations in CTnT, CTnI and CTnC on the Ca2+ regulation of cardiac muscle contraction in our animal models, with the pathogenesis of FHC in humans, especially in cases where sudden cardiac deaths have been reported. These studies will determine the functional consequences of different troponin T, troponin I and troponin C mutations under the same experimental conditions, and thus help identify key mechanism(s) involved in the pathogenesis of Troponin-linked FHC and lead to potential therapeutic strategies