Integrative Approach to Divergent Remodeling in Thin Filament Cardiomyopathies

项目总结： 心脏细丝是心脏收缩和松弛的重要调节器 在分子水平上。它由5个离散蛋白组成：cTnC、cTnI、cTnT、肌动蛋白 和原肌球蛋白共同进化以维持休息时有效的心脏功能， 在锻炼期间，重要的是，对病理性应激源做出反应。基因突变 编码这些蛋白质中的每一种都与一种 人类遗传性心肌病的范围，包括肥厚型(HCM)和扩张型 (DCM)表格。尽管25年来的研究确定了(S)与 生物物理伤害和由此导致的复杂心肌病，许多问题仍然存在 并大大限制了我们使用基因来预测和告知患者的能力 管理层。最近基于基因分型队列的临床研究已经证实 病理性重构的早期阶段先于显性心脏的发展。 肥大或扩张。这一开创性的观察结果提出了一种可能性，即早期 关注最早的分子“触发因素”的治疗干预可能会证明 成功地减缓了这些复杂疾病的自然历史。为了测试这一点 假设，目前的申请建立在我们之前的资助期基础上，我们 开发了一种创新的集成方法来探测细丝连接的HCM和 DCM融合了计算、生物物理学和全心生理学。我们有 确定了两条不同的、共同的致病途径进行研究。在目标1中，我们将描绘 原肌球蛋白重叠区和偶联变构的动力学作用 心肌肌钙蛋白T-N末端对心脏差异性重构的调节 它定义了肥厚型和扩张型心肌病与已知的 弹性原肌球蛋白重叠。在目标2中，我们将定义潜在的调节作用 作为结点的CaMKII信号激活中cTNC钙解离动力学的改变 在肌节肥厚型心肌病的发病机制中具有重要意义。成功者 这些目标的完成既将揭示新的疾病机制，又将直接测试 改变遗传性HCM和DCM自然历史的可能性。

Project Summary: The cardiac thin filament is the essential regulator of cardiac contractility and relaxation at the molecular level. It is comprised of five discrete proteins: cTnC, cTnI, cTnT, actin and tropomyosin that have co-evolved to sustain efficient cardiac performance at rest, during exercise and, importantly, to respond to pathologic stressors. Mutations in genes encoding each of these proteins have been definitively linked to the development of a range of human genetic cardiomyopathies, including hypertrophic (HCM) and dilated (DCM) forms. Despite 25 years of study to define the direct link(s) between the biophysical insult and the resultant complex cardiomyopathy, many questions remain and significantly limit our ability to use genotype to prognosticate and inform patient management. Recent clinical studies based on genotyped cohorts have established that the earliest stages of pathogenic remodeling precedes the development of overt cardiac hypertrophy or dilatation. This seminal observation raises the possibility that early therapeutic intervention focusing on the earliest molecular “triggers” may prove successful in slowing the natural history of these complex disorders. To test this hypothesis, the current application builds on our prior funding period where we developed an innovative integrated approach to probing thin filament-linked HCM and DCM that incorporates computation, biophysics and whole-heart physiology. We have identified two distinct, common pathogenic pathways to study. In Aim 1 we will delineate the dynamic role of the Tropomyosin overlap domain and the coupled allosteric regulation by the cardiac Troponin T N terminus on the differential cardiac remodeling that defines hypertrophic and dilated cardiomyopathies linked to known mutations in the flexible tropomyosin overlap. And in Aim 2 we will define the potential modulatory role of altered cTnC Ca2+ dissociation kinetics in the activation of CaMKII signaling as a nodal point in the pathogenesis of sarcomeric hypertrophic cardiomyopathy. The successful completion of these Aims will both reveal novel disease mechanisms and directly test the potential for altering the natural history of genetic HCM and DCM.