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: 8773592
• 负责人: Jil C Tardiff
• 金额: $ 37.12万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773592
• 关键词: Actins; Actomyosin; Acute; Address; Adrenergic Agents; Adult; Affect; Attention; Binding; Biological Assay; C-terminal; Cardiac; Cardiomyopathies; Cardiovascular system; Clinical; Complex; Computer Simulation; Coupled; Defect; Development; Disease; Distant; Embryo; Energy Transfer; Equilibrium; Familial Hypertrophic Cardiomyopathy; Familial disease; Fiber; Frequencies; Functional disorder; Funding; Gatekeeping; Generations; Genes; Genotype; Goals; Grant; Head; Health; Heart; Heart failure; Hereditary Disease; Human; Hybrids; Hypertrophic Cardiomyopathy; In Vitro; Individual; Infant; Lead; Left Ventricular Hypertrophy; Life; Link; Longevity; Maps; Measurement; Mechanics; Methodology; Microfilaments; Microscopic; Modality; Modification; Mus; Muscle Cells; Mutation; Natural History; Normal Range; Observational Study; Pathogenesis; Patients; Pattern; Phase; Phenotype; Phosphorylation; Point Mutation; Process; Protein Isoforms; Proteins; Regulation; Role; Series; Skin; Stress; Structure; Syndrome; System; Tail; Techniques; Therapeutic; Therapeutic Intervention; Thin Filament; Time; Tissues; Transgenic Mice; Tropomyosin; Troponin; Variant; Ventricular Remodeling; adapter protein; adrenergic; base; cell motility; clinically relevant; dimer; disease-causing mutation; dosage; early onset; end stage disease; experience; fetal; genetic linkage; genetic regulatory protein; improved; in vivo; link protein; mouse model; mutant; novel; prognostic; protein protein interaction; protein structure; sudden cardiac death; tool

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.

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 的个体。临床范围广泛，从正常的心功能和寿命到侵袭性心肌病重构和早期心源性猝死。自 1990 年首次遗传连锁研究以来，所有已知肌节蛋白的突变都被认为是该疾病的病因，并且该疾病的家族型 (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该疾病的子集特别复杂，许多患者不会出现“典型的”左心室肥大，而是经历积极的心室重塑并经历显着频率的心源性猝死。最近，调节性细丝原肌球蛋白 (TM) 的中央“看门人”蛋白携带突变 (Asp230Asn) 的患者已被证明会出现复杂的双峰临床综合征，导致婴儿急性心力衰竭和成人后期出现收缩功能障碍。这种独特的临床表现突出了有关 FHC 发病机制的重要问题，这些问题尚未得到解答。 特别是，复合体水平上细丝调节的主要生物物理缺陷是什么？随着时间的推移，什么调节心室重塑的变化模式？在这笔资助的最后一个资助期内，我们开发了一系列多方面的方法，包括细丝的新颖计算模型、体外运动测定的修改和 独特的小鼠模型使我们能够开发出一种集成的计算机体外体内系统，用于研究从原子到整个心脏水平的细丝突变的影响。我们将这种方法应用于心肌肌钙蛋白突变的子集，发现单个突变的影响可以通过突变蛋白“传播”，以全局影响细丝调节并引起进行性心血管重塑。我们现在将注意力转向 TM 和 cTnT，并通过两个具体目标关注可能参与心肌病重塑最早发展的两种独特疾病机制：1）确定由 TNT1-TM 头尾重叠域已知突变引起的差异性心室重塑的潜在机制，并通过 cTnT 同种型转换来调节 DCM 表型。 体内； 2) 明确高度保守的TNT1 C端“非结构化”结构域的功能作用，并确定该区域突变引起的严重进行性心肌病的致病机制。鉴于在患者发展为终末期疾病之前确定治疗干预点以改变患者这种复杂心肌病的自然史的巨大潜力，这种对早期疾病机制的新关注尤为重要。