ROLE OF MY-BP-C MODULATION OF CARDIAC CONTRACTION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 尽管生物医学取得了进展，但心力衰竭患者的5年死亡率仍远高于50%。编码心肌肌球蛋白结合蛋白-C（cMyBP-C）的基因突变是肥大性心肌病（HCM）的最常见原因，HCM是一种影响1/1，500美国人的疾病。此外，心肌细胞中cMyBP-C的磷酸化改变（即，心肌）可导致遗传性和获得性心肌疾病中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开发新的治疗方法，如基因治疗和控制cMyBP-C结构动力学的药物，以增强力和压力的产生。我们认为cMyBP-C的作用是在收缩周期的速度上“设置中断”，并在磷酸化时在收缩时释放中断。使用同步加速器X射线衍射的方法，我们将探测在基因工程小鼠中去除或改变cMyBP-C所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修饰时，对肌球蛋白结构有深远的影响。我们目前的项目工作集中在使用膜完整的心肌，因为它在活的心脏跳动，在其中，我们将记录抽搐之间的抽搐力和衍射图案和附近的最大抽搐力从小鼠心肌中分离的小梁电刺激的β-肾上腺素能刺激药物的存在和不存在。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。

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.