Mechanisms of myopathy caused by mutations in the myosin rod

肌球蛋白杆突变引起的肌病机制

• 批准号: 7789632
• 负责人: Leslie Anne Leinwand
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-16 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789632
• 关键词: Address; Adult; Amino Acids; Binding Proteins; Biochemical; Biological Assay; C-terminal; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Defect; Dilated Cardiomyopathy; Disease; Doctor of Philosophy; Filament; Genetic; Health; Heart; Heart Diseases; Human; Hypertrophic Cardiomyopathy; In Vitro; Individual; Lead; Mediating; Methods; Modeling; Molecular; Motor; Mus; Mutation; Myocardium; Myopathy; Myosin ATPase; Myosin Heavy Chains; Myosin Light Chains; Myosin Rod; Pathogenesis; Property; Proteins; Public Health; Reaction; Research Personnel; Sarcomeres; Skeletal Muscle; Specificity; Sudden Death; Testing; Thick; Thick Filament; Tissues; Transgenic Mice; disease-causing mutation; mutant; novel; retinal rods; skeletal; theories

DESCRIPTION (provided by applicant): Mutations in sarcomeric proteins such as myosin heavy chain (MyHC) can cause either skeletal or cardiomyopathy. Over 150 mutations in the P MyHC motor domain have been found to cause hypertrophic cardiomyopathy (HCM) while 2 such mutations cause dilated cardiomyopathy (DCM). Despite the expression of p MyHC in both human heart and skeletal muscle, these individuals have little or no skeletal myopathy. Because of the large number of MyHC mutations in the motor domain, the prevailing theory is that HCM caused by MyHC mutations is the result of impaired motor function. However, disease-causing mutations in the rod domain of p MyHC that cause skeletal or cardiomyopathy have recently been discovered and these likely indicate a novel mechanism of pathogenesis. These observations lead to our proposal: to discover how 3 MyHC rod mutations lead to skeletal and cardiomyopathy and how mutations in a protein expressed in both tissues (P MyHC) can cause disease only in skeletal muscle or only in cardiac muscle. The major function of the myosin rod is to mediate the assembly of myosin into the thick filament via its C-terminal third (light meromyosin or LMM). However, the mechanisms and sequence determinants of interaction of MyHC molecules to form the highly ordered thick filament remain obscure. This is due in large part to the absence of methods for isolating and characterizing assembly intermediates and their reaction. We have developed such methods and plan to study the assembly of wild type (WT) and mutant LMMs. We believe that the analysis of these disease causing mutants will be very informative also in defining the mechanisms of myosin filament assembly. To address the tissue specificity of these myopathy mutations, we also propose to test the effects of these mutations on their interactions with tissue-specific myosin binding proteins (MyBPs). We propose to test following hypotheses: Hypothesis I: Myosin rod mutations leading to myopathy impair assembly of the thick filament. Hypothesis II: These dominant mutations will have structural consequences on the sarcomere. Hypothesis III: Myosin rod mutations will impair cardiac myocyte contractility. Hypothesis IV: Mice expressing myosin rod mutations will serve as models for skeletal and cardiomyopathy. Relevance to public health: Genetic heart disease is an important health problem and this specific type of heart disease we study is the leading cause of sudden death in young people.

描述（由申请人提供）：肌球蛋白重链（MYHC）等肌肉蛋白中的突变会导致骨骼或心肌病。发现P MyHC运动结构域中的150多个突变引起肥厚性心肌病（HCM），而2种此类突变引起了扩张的心肌病（DCM）。尽管P MyHC在人心脏和骨骼肌中都表现出来，但这些人几乎没有骨骼肌病。由于运动域中的MYHC突变大量，因此流行的理论是由MyHC突变引起的HCM是运动功能受损的结果。然而，最近发现了引起骨骼或心肌病的P MYHC杆状结构域中引起疾病​​的突变，这些可能表明了一种新型的发病机理。这些观察结果导致了我们的建议：发现3个MyHC棒突变如何导致骨骼和心肌病，以及在两种组织中表达的蛋白质中的突变如何仅在骨骼肌或心脏肌肉中引起疾病​​。肌球蛋白棒的主要功能是通过其C末端第三（轻质毛毛霉素或LMM）介导肌球蛋白的组装到厚细丝中。但是，MyHC分子相互作用形成高度有序的厚细丝的机理和序列决定因素仍然晦涩。这在很大程度上是由于缺乏分离和表征组装中间体及其反应的方法。我们已经开发了这种方法，并计划研究野生型（WT）和突变体LMM的组装。我们认为，对这些引起突变体的疾病的分析也将在定义肌球蛋白丝组装的机制方面非常有用。为了解决这些肌病突变的组织特异性，我们还建议测试这些突变对它们与组织特异性肌球蛋白结合蛋白（MYBP）相互作用的影响。我们建议测试以下假设：假设I：肌球蛋白棒突变，导致肌病损害厚细丝的组件。假设II：这些主导突变将对肌节产生结构性后果。假设III：肌球蛋白棒突变会损害心肌细胞收缩性。假设IV：表达肌球蛋白棒突变的小鼠将作为骨骼和心肌病的模型。与公共卫生有关：遗传心脏病是一个重要的健康问题，我们研究的这种特定类型的心脏病是年轻人猝死的主要原因。