FHC Tn Mutations: Functional Consequences & Mechanisms

家族性肥厚型心肌病（FHC）是一种常染色体显性遗传疾病，几乎所有主要的心肌肌节蛋白都存在突变。肌球蛋白重链（MHC）突变的个体通常具有较高水平的心脏肥大，而具有心肌肌钙蛋白T（CTnT）和一些已报道的肌钙蛋白I（CTnI）突变的个体具有较少的肥大和较高的心脏性猝死（SCD）发生率。 最近，肌钙蛋白C中的一个突变被报道可能与FHC相关。尽管几种突变已在体外得到广泛表征，但仍不清楚它们如何引起心脏肥大或SCD。 我们的工作假设是，FHC肌钙蛋白突变改变pCa力和ATP酶的关系，肌肉的能力，发展最大的力量和ATP酶活性，肌球蛋白跨桥动力学，收缩效率，和肌肉的能力做工作。 增加Ca 2+敏感性的突变与猝死的关系更密切，而降低肌肉产生力量的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沿着我们来自表达人CTnT（HCTnT）FHC突变（I79 N、F1101和R278 C）和HCTnI-R145 G的三个转基因小鼠系的数据，支持这一假设。 本提案的目的是全面研究体外结果（例如，收缩的Ca 2+敏感性、力发展/舒张动力学、CTnI抑制功能受损等）。在现有的和新的转基因小鼠中不同的FHC相关肌钙蛋白突变，以确定参与FHC发病机制的关键机制。这项申请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。我们的目标是将在我们的动物模型中观察到的CTnT、CTnI和CTnC突变对心肌收缩的Ca 2+调节的影响与人类FHC的发病机制相关联，特别是在已报道的心脏性猝死的情况下。 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