ROLE OF CMYBP-C IN THE REGULATION OF MYOCARDIUM

CMYBP-C 在心肌调节中的作用

• 批准号: 7722750
• 负责人: Richard L Moss
• 金额: $ 5.06万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7722750
• 关键词: Affect; American; Cardiac; Cardiac Myocytes; Cardiac Myosins; Charge; Computer Retrieval of Information on Scientific Projects Database; Contracts; Development; Disease; Drug Controls; Familial Hypertrophic Cardiomyopathy; Funding; Genes; Genetically Engineered Mouse; Grant; Growth; Health; Heart; Heart failure; Hereditary Disease; Institution; Laboratories; Lead; Left; Location; Molecular; Molecular Conformation; Molecular Structure; Mus; Muscle Cells; Mutation; Myocardial Contraction; Myocardium; Patients; Protein Conformation; Proteins; Regulation; Research; Research Personnel; Resources; Role; Source; Speed; Thick; United States National Institutes of Health; Ventricular; X ray diffraction analysis; X-Ray Diffraction; beamline; gene therapy; mortality; myosin-binding protein C

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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 由心肌肌球蛋白结合蛋白C(cMyBP-C)基因突变引起的家族性肥厚性心肌病(FHC)估计每1500名美国人中就有一人受到影响。这种遗传性心脏疾病的特征是左室壁厚度增加。尽管经过了30多年的研究，但cMyBP-C在肌肉细胞中的确切结构位置和功能仍远不清楚。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，随着健康和疾病的变化，cMyBP-C已被改变以模仿这种蛋白质的构象。 我们相信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)，我们将探索由于移除或改变我们的基因工程小鼠的cMyBP-C而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的构象也会影响心脏功能，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电荷引起的结构变化。 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在调节心脏收缩中的作用可以导致开发新的治疗方法，如基因疗法和控制cMyBP-C构象的药物。