Calcium Dependent Gene Expression in Muscle

描述（由申请人提供）： 该提案描述了一个为期四年的分子心脏病学学术生涯的培训计划。 主要研究者已完成内科住院医师和临床心脏病学的临床培训，并接受了心力衰竭/移植方面的额外培训。 他还在赞助商R。医学博士桑德斯威廉姆斯 在此期间，主要研究者已经发展了分子生物学和细胞生理学的基本技能，以建立一个专注于肌细胞钙成像的项目。 指导临床科学家发展奖是一个很好的机会，以进一步他的科学发展博士威廉姆斯。 申办者是位于北卡罗来纳州达勒姆的杜克医学院的院长和心脏和骨骼肌生物学专家。 多年来，他成功地指导了许多分子心脏病专家、博士后研究员、研究生和初级教员。 该计划将建立在过去两年开始的广泛培训的基础上，重点关注肌肉肥大和专业化模型中的钙信号传导和转录激活。 威廉姆斯实验室的工作已经建立了基因表达的神经激活和钙调节的丝氨酸-苏氨酸磷酸酶，钙调神经磷酸酶之间的联系。 功能丧失和功能获得的研究已经建立了钙调磷酸酶途径作为一个关键的节点兴奋转录偶联。 该计划的研究将集中在钙调磷酸酶途径的近端方面，以了解钙激活并确定肌肉中该途径的上游方面。 具体目标将包括：1）确定调节分离的单纤维和心肌细胞中钙调神经磷酸酶和NFAT信号传导的钙信号传导的空间和时间方面，2）定义完整动物中负责NFAT激活的钙信号，3）鉴定在特定肌纤维亚型中差异表达且在基因调节中很重要的钙信号传导分子。 这项研究将建立一个更好的理解钙信号及其对心脏和骨骼肌病变的影响。 在杜克大学心脏病学分部建立的培训环境表明了对年轻教师职业发展的持续承诺，特别是在分子心脏病学方面。

DESCRIPTION (provided by applicant): This proposal describes a four-year training program for an academic career in molecular cardiology. The principal investigator has completed clinical training in internal medicine residency as well as clinical cardiology with additional training in heart failure/transplantation. He has also completed two additional years of post-doctoral work in the laboratory of the sponsor, R. Sanders Williams, M.D. During this time the principal investigator has developed fundamental skills in molecular biology and cellular physiology in order to establish a program focusing on calcium imaging in myocytes. The Mentored Clinical Scientist Development Award is an excellent opportunity to further his scientific development under Dr. Williams. The sponsor is the Dean of Duke Medical School in Durham, NC and an expert in cardiac and skeletal muscle biology. He has successfully mentored numerous molecular cardiologists, post-doctoral fellows and graduate students and junior faculty members over the years. This program will build on the extensive training initiated over the last two years and focus on calcium signaling and transcriptional activation in models of muscle hypertrophy and specialization. Work in the Williams' laboratory has established the link between neural activation of gene expression and the calcium regulated serine-threonine phosphatase, calcineurin. Loss of function and gain of function studies have established the calcineurin pathway as a critical nodal point for excitation transcription coupling. Research in this program will focus on the proximal aspects of the calcineurin pathway in order to understand calcium activation and identify upstream aspects of this pathway in muscle. Specific aims will include: 1) to determine the spatial and temporal aspects of calcium signaling that regulate calcineurin and NFAT signaling in isolated single fibers and cardiomyocytes, 2) to define the calcium signals responsible for NFAT activation in an intact animal, 3) to identify calcium signaling molecules that are differentially expressed among specialized myofiber subtypes and are important in gene regulation. The research proposed will establish a better understanding of calcium signaling and its influence on cardiac and skeletal myopathies. The training environment established in the Division of Cardiology at Duke University has demonstrated a continued commitment to the career development of young faculty, particularly in molecular cardiology.