Role of Homer Proteins in Calcium Signaling in Muscle

荷马蛋白在肌肉钙信号传导中的作用

• 批准号: 7468355
• 负责人: JONATHAN A STIBER
• 金额: $ 12.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468355
• 关键词: Academic Medical Centers; Adult; Affect; Calcineurin; Calcium; Calcium Signaling; Calmodulin; Cardiac; Cardiology; Cell Surface Proteins; Cell physiology; Clinical; Development; Disruption; Embryo; Embryonic Development; Event; Faculty; Family; Fiber; Gene Expression; Goals; Heart Hypertrophy; Homer protein; Internal Medicine; Investigation; Laboratories; Link; Mediating; Medicine; Memory; Mentors; Metabolism; Modeling; Molecular; Molecular Biology; Mus; Muscle; Muscle Fibers; Muscle function; Myocardium; Myopathy; Names; Pattern; Phosphoric Monoester Hydrolases; Physiological; Play; Postdoctoral Fellow; Prevention; Principal Investigator; Protein Isoforms; Protein Overexpression; Protein Serine/Threonine Phosphatase; Proteins; Regulation; Research Personnel; Research Training; Role; Ryanodine Receptor Calcium Release Channel; Scaffolding Protein; Series; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal system; Stimulus; Striated Muscles; Students; Testing; Title; Training; Training Programs; Universities; career; gain of function; in vivo; loss of function; mRNA Expression; membrane excitation; mouse model; pressure; programs; receptor; response; tissue culture; transcription factor

DESCRIPTION (provided by applicant): This proposal describes a five year training program for an academic career in molecular cardiology. The principal investigator has completed clinical training in internal medicine and cardiology at Duke University Medical Center and has been named to the faculty of the Department of Medicine of Duke University with the title of Associate of Medicine. The principal investigator has spent the last two years in the laboratory of R. Sanders Williams obtaining research training in molecular biology and cellular physiology. The sponsor, Dr. R. Sanders Williams has successfully mentored numerous graduate students, post-doctoral fellows, and cardiologists who have gone on to careers in academic medicine. The Division of Cardiology at Duke University has also demonstrated a strong commitment to the development of academic careers of young faculty. Calcineurin, a calcium regulated serine threonine phosphatase, modulates profiles of gene expression in skeletal and cardiac muscle associated with fiber type differentiation and cardiac hypertrophy. Homer proteins are a family of scaffolding proteins which play a critical role in calcium signaling by mediating the interaction between cell surface proteins and receptors on the SR/ER such as the IP3 and ryanodine receptors. The goal of this project is to determine the role of Homer proteins in regulating calcineurin signaling and its effects on muscle remodeling and cardiac hypertrophy. The Specific Aims are as follows: 1) To characterize the spatial and temporal patterns of expression of Homer isoforms in striated muscle during embryonic development and in response to physiologic stimuli. 2) To determine the role of Homer proteins in myotube development and calcineurin signaling in a tissue culture model. Here we will assess our hypothesis that Homer isoforms influence myotube development, calcium signaling, and activation of the calcineurin/NFAT signaling pathway. 3) To determine the effect of both overexpression and targeted disruption of Homer isoforms on cardiac and skeletal muscle function in mouse models. Here we will use a gain of function/loss of function strategy to determine the role of Homer proteins in vivo in the remodeling events associated with fiber-type differentiation and cardiac hypertrophy.

描述（由申请人提供）： 该建议描述了一个为期五年的分子心脏病学学术生涯的培训计划。首席研究员已在杜克大学医学中心完成内科和心脏病学的临床培训，并以医学副校区的头衔被任命为杜克大学医学系的学院。首席研究者在过去的两年中在R. Sanders Williams实验室中度过了分子生物学和细胞生理学研究培训。赞助商R. Sanders Williams博士成功地指导了众多研究生，博士后研究员以及从事学术医学职业的心脏病专家。杜克大学心脏病学系也表现出对年轻教师学术职业发展的坚定承诺。 钙调节的钙调节丝氨酸苏氨酸磷酸酶，调节与纤维类型分化和心脏肥大相关的骨骼肌和心脏肌肉中基因表达的特征。荷马蛋白是脚手架蛋白的家族，通过介导细胞表面蛋白与SR/ER上的受体之间的相互作用，例如IP3和ryanodine受体，在钙信号传导中起关键作用。该项目的目的是确定荷马蛋白在调节钙调蛋白信号传导及其对肌肉重塑和心脏肥大的影响。具体目的如下：1）表征在胚胎发育过程中肌肉肌肉中本质同工型表达的空间和时间模式，并响应生理刺激。 2）确定荷马蛋白在组织培养模型中肌管发育和钙调蛋白信号传导中的作用。在这里，我们将评估我们的假设，即荷马同工型会影响肌管发育，钙信号传导以及钙调神经酶/NFAT信号通路的激活。 3）确定在小鼠模型中，荷马同工型的过表达和靶向破坏对心脏和骨骼肌功能的影响。在这里，我们将利用功能/功能策略的损失来确定荷马蛋白在体内在与纤维类型分化和心脏肥大相关的重塑事件中的作用。