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NRSA个人资助，目前是马里兰州大学生物化学与分子生物学系的研究助理。他的职业目标是建立一个多产，独立的，额外资助的实验室，其重点是研究正常和病理肌肉中E-C耦合的基本机制。拟议的指导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。本研究的主要目的是探讨钙调素（CaM）及其结合结构域在电压依赖性L型钙通道（DHPR）和骨骼肌肌浆网钙释放通道（Ryanodine receptor，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Ca 2+结合蛋白CaM的结合位点，并且RyR在功能上受CaM调节。此外，最近的数据表明，DHPR和RyR之间的机械耦合可能会发生，部分，通过其钙调素结合域。为了阐明钙调素在调节骨骼肌钙动员中的作用，提出了三个具体的目标。1)检查钙调素在调节电压激活与Ca 2+激活的SR Ca 2+释放中的作用。2)检查钙调素调节SR Ca 2+释放的RyR亚型依赖性。3)表征DHPR和RyR内的钙调素结合结构域对SR Ca 2+释放和E-C偶联的贡献。这项研究将在马里兰州大学医学院进行，该学院拥有研究肌肉中Ca 2+信号的国内和国际知名科学家以及荧光共聚焦显微镜的最先进设施。赞助人马丁·施耐德博士是肌肉研究领域的资深研究员，也是NIH-NIAMS资助的肌肉生物学培训项目的负责人。在施耐德博士及其高级研究人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.