ROLE OF MY-BP-C MODULATION OF CARDIAC CONTRACTION

MY-BP-C 调节心脏收缩的作用

• 批准号: 8168615
• 负责人: Richard L Moss
• 金额: $ 6.29万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168615
• 关键词: Adrenergic Agents; Affect; American; Cardiac; Cardiac Myocytes; Cardiac Myosins; Cardiomyopathies; Computer Retrieval of Information on Scientific Projects Database; Contracts; Development; Disease; Drug Controls; Functional disorder; Funding; Generations; Genes; Genetically Engineered Mouse; Grant; Heart; Heart failure; Hypertrophic Cardiomyopathy; Institution; Kinetics; Lead; Life; Membrane; Molecular Structure; Mus; Mutation; Myocardium; Myosin ATPase; Patients; Pattern; Pharmaceutical Preparations; Phosphorylation; Research; Research Personnel; Resources; Role; Source; Speed; Synchrotrons; Thin Filament; United States National Institutes of Health; adrenergic; gene therapy; mortality; myosin-binding protein C; pressure; protein structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite advances in biomedicine, the 5-year mortality of heart failure patients remains well above 50%. Mutations in the gene encoding cardiac myosin binding protein-C (cMyBP-C) is the most common cause of hypertrophic cardiomyopathies (HCM), a disease which affects 1 in 1,500 Americans. In addition, the altered phosphorylation of cMyBP-C in heart muscle cells (i.e., myocardium) can contribute to compensatory mechanisms and contractile dysfunction in heritable and acquired myocardial disease. Thus, understanding cMyBP-C's role in modulating contraction could lead to development of new treatments such as gene therapy and drugs controlling the structural dynamics of cMyBP-C to enhance force and pressure generation. We believe cMyBP-C acts to "put the breaks" on the speed of the contracting cycle and releases the break on contraction when phosphorylated. Using the approach of synchrotron x-ray diffraction, we will probe for changes in molecular structure that arises from removing or altering cMyBP-C in genetically-engineered mice. In support of our hypothesis, we have already found profound effects on the myosin protein structure when cMyBP-C is lacking or modified using de-membrantaed myocardium. Our present project efforts focus on using membrane-intact myocardium as it beats in the living heart, in which we will record twitch force and diffraction patterns in between twitches and near maximum twitch force in trabeculae isolated from mouse myocardium electrically stimulated in the presence and absence of a beta-adrenergic-stimulating drug. We hypothesize that treatment will move cross-bridges towards the thin filament before the twitch to accelerate contraction kinetics on contraction.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 尽管生物医学取得了进步，心力衰竭患者的 5 年死亡率仍然远高于 50%。编码心肌肌球蛋白结合蛋白-C (cMyBP-C) 的基因突变是肥厚型心肌病 (HCM) 的最常见原因，这种疾病影响着每 1,500 名美国人中就有 1 人。此外，心肌细胞（即心肌）中 cMyBP-C 磷酸化的改变可能会导致遗传性和获得性心肌疾病的代偿机制和收缩功能障碍。因此，了解 cMyBP-C 在调节收缩中的作用可能会导致新疗法的开发，例如基因疗法和控制 cMyBP-C 结构动力学的药物，以增强力和压力的产生。我们相信 cMyBP-C 的作用是“中断”收缩周期的速度，并在磷酸化时释放收缩中断。利用同步加速器 X 射线衍射的方法，我们将探究基因工程小鼠中因去除或改变 cMyBP-C 而引起的分子结构变化。 为了支持我们的假设，我们已经发现当 cMyBP-C 缺乏或使用去膜心肌进行修饰时，会对肌球蛋白结构产生深远影响。我们目前的项目工作重点是使用在活体心脏中跳动的膜完整的心肌，其中我们将记录从存在和不存在β-肾上腺素刺激药物的情况下电刺激的小鼠心肌中分离出的小梁中的抽搐和接近最大抽搐力之间的抽搐力和衍射图案。我们假设治疗将在抽搐之前将横桥移向细丝，以加速收缩时的收缩动力学。