Calmodulin & Calmodulin Binding Domains in E-C Coupling

描述(由申请人提供)： 候选人乔治·罗德尼博士是一名生理学家，由个人NRSA资助，目前是马里兰大学生物化学和分子生物学系的副研究员。他的职业目标是发展一个富有成效的、独立的、由外部资金资助的实验室，其重点将是研究正常肌肉和病理肌肉中E-C偶联的基本机制。拟议的导师研究科学家发展奖将提供实现这些目标所需的必要专业和研究技能。本研究旨在探讨钙调素(CaM)及其结合域在电压依赖性L钙通道(DHPR)和骨骼肌肌浆网钙释放通道(RyR)调节骨骼肌兴奋收缩偶联中的作用。DHPR和RyR都含有普遍存在的钙结合蛋白CaM的结合位点，RyR的功能受CaM调控。此外，最近的数据表明，DHPR和RyR之间的机械耦合可能部分通过它们的CaM结合结构域发生。为了阐明CaM在骨骼肌钙离子动员调节中的作用，我们提出了三个特定的靶点。1)研究钙调素在调节电压激活与钙激活的肌浆网钙释放中的作用。2)研究钙调素调节肌浆网钙释放的RyR亚型依赖关系。3)研究DHPR和RyR内钙调蛋白结合域在肌质网钙释放和E-C偶联中的作用。这项研究将在马里兰大学医学院进行，该学院拥有国内外著名的研究肌肉中钙信号的科学家，以及最先进的荧光共聚焦显微镜设备。发起人马丁·施耐德博士是肌肉研究领域的知名研究员，也是NIH-NIAMS资助的肌肉生物学培训项目的负责人。在施耐德博士和他的高级研究员咨询委员会的专家指导下，罗德尼博士将发展必要的专业和研究技能，以领导骨骼肌生物学领域的杰出和富有成效的职业生涯。

DESCRIPTION (provided by applicant): The candidate, George Rodney, Ph.D., is a physiologist who has been funded by an Individual NRSA and is currently a Research Associate in the Department of Biochemistry & Molecular Biology at the University of Maryland. His career goal is to develop a productive, independent, extramurally funded laboratory, the focus of which will be to study the basic mechanisms of E-C coupling in both normal and pathological muscle. The proposed Mentored Research Scientist Development Award will provide the necessary professional and research skills needed to achieve these goals. The general goal of this proposal is to critically examine the role of calmodulin (CaM) and the CaM binding domains within the voltage dependent L-type Ca2+ channel (DHPR) and the skeletal muscle sarcoplasmic reticulum Ca2+ release channel (ryanodine receptor, RyR) in modulating skeletal muscle excitation-contraction coupling. Both the DHPR and RyR contain binding sites for the ubiquitous Ca2+ binding protein CaM and RyR is functionally modulated by CaM. Furthermore, recent data suggest that the mechanical coupling between the DHPR and RyR may occur, in part, through their CaM binding domains. To elucidate the role of CaM in the modulation of Ca2+ mobilization in skeletal muscle three specific aims are proposed. 1) Examine the role of calmodulin in modulating voltage activated versus Ca2+ activated SR Ca2+ release. 2) Examine the RyR isoform dependence of calmodulin's modulation of SR Ca2+ release. 3) Characterize the contribution of calmodulin binding domains within the DHPR and RyR on SR Ca2+ release and E-C coupling. This research will be conducted at the University of Maryland School of Medicine, which houses nationally and internationally renowned scientist studying Ca2+ signaling in muscle as well as state-of-the-art facilities in fluorescent confocal microscopy. The sponsor, Martin Schneider Ph.D., is an established investigator in muscle research and is the director of a NIH-NIAMS funded training program in muscle biology. Under the expert guidance of Dr. Schneider and his Advisory Committee of senior investigators Dr. Rodney will develop the necessary professional and research skills needed to lead an outstanding and productive career in skeletal muscle biology.