Integrative Approach to Divergent Remodeling in Thin Filament Cardiomyopathies

细丝心肌病发散性重构的综合方法

基本信息

批准号：
8843918
负责人：
Jil C Tardiff
金额：
$ 37.31万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8843918
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

项目摘要

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，影响了1/500个个体。临床光谱范围很大，从正常的心脏功能和寿命到侵略性的心肌病重塑和早期心脏死亡。自1990年首次进行遗传连锁研究以来，所有已知的肉瘤蛋白的突变被认为是该疾病的因果关系，并且该疾病的家族形式（FHC）被认为占所有病例的50％以上。长期以来，人们一直注意到，由薄丝蛋白突变引起的疾病子集特别复杂，因此许多患者没有发展“经典”左心室肥大，而是经历侵袭性的心室重塑并经历了突然心脏死亡的显着频率。最近，在调节性细丝的中央“看门人”蛋白中携带突变（ASP230ASN）的患者已显示出一种复杂的双峰临床综合征，从而导致婴儿的急性心脏衰竭，并在成人临床上造成的临床症状问题。特别是，在薄丝调节的水平上，哪些主要的生物物理缺陷是什么来调节随时间的时间的室中重塑的变化？我们开发了一系列多面方法学方法独特的小鼠模型，使我们能够开发一种在体外系统中积分的硅体内，以研究从原子能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脏肌钙蛋白突变的一部分，发现可以通过突变蛋白“传播”单个突变的效果，以影响全球影响薄丝细丝调节并引起渐进性心血管重塑。 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体内2）定义高度保守的TNT1 c-末端“非结构化”结构域的功能作用，并确定由该区域突变引起的严重，进行性心肌病的致病机制。考虑到鉴定治疗干预点以改变患者在患者发生终末期疾病之前改变这种复杂心肌病的自然病史的高潜力，这种对早期疾病机制的新关注尤其重要。