ROLE OF CMYBP-C IN THE REGULATION OF MYOCARDIUM

这个子项目是许多研究子项目中的一个 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。 由编码心肌肌球蛋白结合蛋白C（cMyBP-C）的基因突变引起的家族性肥厚型心肌病（FHC）估计影响1，500名美国人。 这种心脏遗传性疾病的特征是左心室壁厚度增加。 尽管经过30多年的研究，cMyBP-C在肌肉细胞中的确切结构位置和功能还远未明确。 我们的研究调查了基因工程小鼠心脏的结构变化，这些小鼠缺乏cMyBP-C或具有cMyBP-C，该cMyBP-C已被改变以模仿这种蛋白质在健康和疾病中的构象变化。 我们认为cMyBP-C的作用是“打破”心肌细胞收缩周期的速度。 使用X射线衍射方法（在阿贡国家实验室的BioCAT光束线上），我们将探测在我们的基因工程小鼠中去除或改变cMyBP-C引起的心肌细胞分子结构的变化。 为了支持我们的假设，我们已经发现了对缺乏这种蛋白质的小鼠的分子结构的深远影响。 此外，改变cMyBP-C的构象会影响心脏功能，这可能是由于其分子“电荷”的变化。 因此，我们将研究改变cMyBP-C上的电荷所引起的结构变化。 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%。 因此，了解cMyBP-C在控制心脏收缩中的作用可以导致开发新的治疗方法，如基因治疗和控制cMyBP-C构象的药物。

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. Familial hypertrophic cardiomyopathy (FHC) caused by mutation in the gene encoding cardiac myosin binding protein-C (cMyBP-C) is estimated to affect one in 1,500 Americans. This genetic disorder of the heart is characterized by increased growth in thickness of the left ventricular wall. Despite over 30 years of research, the exact structural location and function of cMyBP-C in muscle cells is far from clear. Our research investigates the structural changes in hearts from genetically-engineered mice which lack cMyBP-C or have cMyBP-C that has been altered to mimic this protein's conformation as it changes in health and disease. We believe cMyBP-C acts to "put the breaks" on the speed of the contracting cycle in heart muscle cells. Using the approach of X-ray diffraction (on the BioCAT beamline, Argonne National Laboratory), we will probe for changes in the molecular structure of heart muscle cells that arise from removing or altering cMyBP-C in our genetically-engineered mice. In support of our hypothesis, we have already found profound effects on the molecular structure in mice lacking this protein. Additionally, altering the conformation of cMyBP-C affects cardiac function, which may be due to changes in its molecular "charge". We will therefore examine structural changes arising from changing the charge on cMyBP-C. Despite advances in biomedicine, the 5-year mortality of heart failure patients remains well above 50%. Thus, understanding the role of cMyBP-C in governing contraction of the heart can lead to development of new treatments such as gene therapy and drugs that control the conformation of cMyBP-C.