Integrative Approach to Divergent Remodeling in Thin Filament Cardiomyopathies

细丝心肌病发散性重构的综合方法

• 批准号: 10153861
• 负责人: Jil C Tardiff
• 金额: $ 46.82万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153861
• 关键词: Actins; Actomyosin; Allosteric Regulation; Alternative Splicing; Biophysics; Calcium; Cardiac; Cardiomyopathies; Chest; Clinical; Clinical Research; Complex; Coupled; Couples; Development; Differential Scanning Calorimetry; Dilatation - action; Dilated Cardiomyopathy; Disease; Disease Progression; Dissociation; Exercise; Exhibits; Fiber; Fluorescence Resonance Energy Transfer; Funding; Gene Mutation; Genes; Genotype; Heart; Heart Hypertrophy; Human Genetics; Hypertrophic Cardiomyopathy; In Vitro; Individual; Intervention; Kinetics; Lead; Link; Measurement; Measures; Mediating; Modeling; Molecular; Mutation; N-terminal; Natural History; Nodal; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Peptides; Performance; Phenotype; Phosphorylation; Physiology; Positioning Attribute; Proteins; Relaxation; Research; Resolution; Rest; Role; SERCA2a; Seminal; Signal Transduction; Site; Skin; Symptoms; System; Testing; Tetanus Helper Peptide; Therapeutic; Therapeutic Intervention; Thin Filament; Time; Tropomyosin; Troponin T; Ventricular Remodeling; Work; base; calmodulin-dependent protein kinase II; cell motility; clinically relevant; cohort; design; efficacy testing; fetal; flexibility; genotyped patients; improved; in silico; in vivo; inherited cardiomyopathy; inhibitor/antagonist; innovation; insight; mouse model; new therapeutic target; novel; prevent; reconstitution; sarcomeric cardiomyopathy; stressor; uptake

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.

项目概要： 心脏细丝是心脏收缩和舒张的重要调节器 在分子水平上。它由五种离散蛋白质组成：cTnC、cTnI、cTnT、肌动蛋白 和原肌球蛋白共同进化以维持静息时有效的心脏功能， 在运动期间，重要的是，对病理应激源做出反应。基因突变 编码这些蛋白质中的每一种都与 一系列人类遗传性心肌病，包括肥厚型心肌病 (HCM) 和扩张型心肌病 (DCM) 形式。尽管经过 25 年的研究才确定了两者之间的直接联系 生物物理损伤和由此产生的复杂心肌病，仍然存在许多问题 并极大地限制了我们使用基因型来预测和告知患者的能力 管理。最近基于基因分型队列的临床研究已经证实 致病性重塑的最早阶段先于明显的心脏疾病的发展 肥大或扩张。这一开创性的观察提出了一种可能性，即早期 专注于最早的分子“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史。为了测试这个 假设，当前的申请建立在我们之前的资助期间 开发了一种创新的集成方法来探测细丝连接的 HCM，并且 DCM 融合了计算、生物物理学和全心生理学。我们有 确定了两种不同的、常见的致病途径进行研究。在目标 1 中，我们将描绘 原肌球蛋白重叠域和耦合变构的动态作用 心肌肌钙蛋白 T N 末端对心脏重构差异的调节 定义了与已知突变相关的肥厚型和扩张型心肌病 柔性原肌球蛋白重叠。在目标 2 中，我们将定义潜在的调节作用 作为节点激活 CaMKII 信号传导过程中 cTnC Ca2+ 解离动力学发生改变 肌节肥厚型心肌病发病机制的关键点。成功者 这些目标的完成将揭示新的疾病机制并直接测试 改变遗传性 HCM 和 DCM 自然史的潜力。