Integrative Approach to Divergent Remodeling in Thin Filament Cardiomyopathies

描述（由申请人提供）：肥厚性心肌病（HCM）是一种相对常见的疾病，影响1/500个体。临床范围广泛，从正常的心功能和寿命到侵袭性心肌病重塑和早期心源性猝死。自1990年首次进行遗传连锁研究以来，所有已知的肉瘤蛋白突变都被认为是该病的病因，家族性疾病（FHC）被认为占所有病例的50%以上。人们早就注意到，由细丝蛋白突变引起的疾病亚群特别复杂，因此许多患者不会发展为“经典”左心室肥厚，而是经历侵袭性心室重构，并经历显著频率的心源性猝死。最近，在调节细丝原肌球蛋白（TM）的中心“看门人”蛋白中携带突变（Asp230Asn）的患者已被证明发展为复杂的双峰临床综合征，导致婴儿急性心力衰竭和成人收缩功能障碍的晚期发展。这一独特的临床表现突出了关于FHC发病机制的重要问题，这些问题仍未得到解答，特别是，在复体水平上，细丝调节的主要生物物理缺陷是什么，是什么调节了心室重构随时间的变化模式？在本基金的最后一个资助期，我们开发了一系列多方面的方法方法，包括一种新的细丝计算模型，对体外运动试验的修改和

DESCRIPTION (provided by applicant): Hypertrophic Cardiomyopathy (HCM) is a relatively common disorder, affecting 1/500 individuals. The clinical spectrum is vast, ranging from normal cardiac function and lifespan to aggressive cardiomyopathic remodeling and early sudden cardiac death. Since the first genetic linkage study in 1990, mutations in all of the known sarcomeric proteins have been implicated as causal for the disease and the familial form of the disorder (FHC) is thought to comprise over 50% of all cases. It has long been noted that the subset of the disease caused by mutations in the thin filament proteins is particularly complex, whereby many patients do not develop the "classic" left ventricular hypertrophy, but instead undergo aggressive ventricular remodeling and experience a significant frequency of sudden cardiac death. More recently, patients carrying a mutation (Asp230Asn) in the central "gatekeeper' protein of the regulatory thin filament, tropomyosin (TM) have been shown to develop a complex bimodal clinical syndrome, resulting in acute cardiac failure in infants and a late development of systolic dysfunction in adults. This unique clinical presentation highlights important questions regarding the pathogenesis of FHC that remain unanswered, in particular, what is the primary biophysical defect in thin filament regulation at the level of the complex and what regulates the changing patterns of ventricular remodeling over time? In the last funding period of this grant we developed a series of multifaceted methodological approaches including a novel computational model of the thin filament, a modification of the in vitro motility assay and unique mouse models that enabled us to develop an integrated in silico - in vitro - in vivo system for studying the effects of thin filament mutations from the atomic to whole-heart levels. We applied this approach to a subset of cardiac troponin mutations and found that the effects of single mutations can be "propagated" through the mutant proteins to globally affect thin filament regulation and cause progressive cardiovascular remodeling. We now turn our attention to both TM and cTnT and focus on two unique disease mechanisms that are likely to be involved in the earliest development of cardiomyopathic remodeling via two Specific Aims: 1) To determine the mechanism(s) underlying the differential ventricular remodeling caused by known mutations in the TNT1-TM head-to-tail overlap domain and to modulate the DCM phenotype via cTnT isoform-switching in vivo; 2) To define the functional role of the highly conserved TNT1 C- terminal "unstructured" domain and determine the pathogenic mechanism underlying the severe, progressive cardiomyopathies caused by mutations in this region. This new focus on early disease mechanisms is particularly important given the high potential for identifying points of therapeutic intervention to change the natural history of this complex cardiomyopathy in patients before they develop end-stage disease.