The role of the C3 domain of myosin binding protein-C in the pathogenesis of hypertrophic cardiomyopathy

肌球蛋白结合蛋白-C C3结构域在肥厚型心肌病发病机制中的作用

• 批准号: 9049810
• 负责人: Dan F Smelter
• 金额: $ 3.06万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049810
• 关键词: Actins; Adrenergic Agents; Affect; Affinity; Amino Acid Sequence; Amino Acid Substitution; Amino Acids; Binding; Binding Proteins; Biological Assay; Biomedical Research; C-terminal; C10; Calcium; Cardiac; Cardiac Myocytes; Cardiac Myosins; Cardiovascular Diseases; Charge; Complement 3c; Contractile Proteins; Development; Disease; Disease Progression; Engineering; Environment; Face; Familial Hypertrophic Cardiomyopathy; Gene Transfer; Head; Health; Heart; Heart Diseases; Human; Hypertrophic Cardiomyopathy; Immunoprecipitation; Individual; Inherited; Laboratories; Lead; Ligands; Light; Link; Location; Messenger RNA; Missense Mutation; Molecular; Mus; Mutation; Myosin ATPase; N-terminal; Neonatal; Pathogenesis; Pathologic; Peptide Sequence Determination; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Property; Protein Binding Domain; Protein Region; Proteins; Proteomics; Regulation; Reporting; Research; Research Proposals; Role; Sarcomeres; Scientist; Structure; Surface; Surface Plasmon Resonance; Testing; Thick Filament; Tissues; Training Programs; Transcript; Universities; Vertebral column; Wisconsin; adenoviral-mediated; citrate carrier; genetic regulatory protein; heart function; insight; interest; mutant; myosin-binding protein C; novel; pre-doctoral; prevent; protein expression; protein protein interaction; public health relevance; restraint; sudden cardiac death; treatment strategy

 DESCRIPTION (provided by applicant): Cardiac myosin binding protein C (cMyBP-C) is a regulatory protein of the cardiac sarcomere that contributes to contractile reserve. Mutations in cMyBP-C are a leading cause of hypertrophic cardiomyopathy (HCM), a disease that affects about 1 in 500 people worldwide. Truncation mutations in cMyBP-C cause HCM primarily through haploinsufficiency; however, the pathogenesis of disease-causing missense mutations is not well understood. The C-terminal domains are essential for incorporation into the sarcomere, while the N-terminal domains modulate contraction through phosphorylation-dependent inhibitory interactions. The role of the central domains in the physiologic function of cMyBP-C is unclear. The R495Q and R502W mutations in the C3 domain of cMyBP-C are among the most prevalent causes of HCM, however exactly how they affect function and contribute to the pathologic phenotype remains unknown. Studies suggest that mutations in this region may disrupt a putative protein binding domain. Given their location in the C3 domain we hypothesize that the R495Q and R502W mutations modulate contractility by modifying an interaction between domain C3 and an as-yet undefined ligand. In this pre-doctoral proposal, we will express mutant R495Q and R502W cMyBP-C in murine three-dimensional cardiac tissue constructs followed by assessment of contractility, calcium handling, calcium sensitivity and responsiveness to beta-adrenergic stimulation. To identify the mechanism linking these mutations to HCM, we will use contemporary proteomics approaches to define the function of the C3 domain and assess whether these mutations alter putative protein-protein interactions. Determining the function of the C3 domain will provide insight into the overall function of cMyBP-C, the pathogenesis of HCM, and may identify novel treatment strategies to prevent or modify disease progression. This pre-doctoral research proposal is part of a comprehensive training program which takes full advantage of the strong research environment at the University of Wisconsin-Madison to enhance the candidate's likely transition to a successful biomedical research scientist.

 描述（由申请人提供）：心脏肌球蛋白结合蛋白C（CMYBP-C）是Cardiaac Saromere的调节蛋白，CMYBP-C中的突变是肥大性心肌病（HCM）的主要原因。在全球范围内，CMYBP-C中的曲折突变主要理解为疾病的任务突变。不清楚的是CMYBP-C的C3结构域中的R495Q和R502W突变是HCM的最普遍的原因，但是情感功能和病理表型可能会破坏假定的蛋白质结合。域C3和尚未定义的配体之间的三二二聚体心脏组织组织，然后评估收缩力，钙处理，钙敏感性和对β肾上腺刺激的响应。 C3结构域并评估这些突变的高度蛋白质 - 蛋白质相互作用。威斯康星州候选人可能过渡到成功的生物医学研究人员。