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: 7111006
• 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/7111006
• 关键词: biological models; calcineurin; calcium channel; calcium flux; developmental genetics; gene expression; genetic manipulation; heart enlargement; heart function; laboratory mouse; mammalian embryology; membrane proteins; molecular pathology; muscle; muscle function; muscle hypertrophy; myotubes; neuropeptides; protein isoforms; protein protein interaction; protein structure function; striated muscles; tissue /cell culture; ventricular hypertrophy

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）： 该提案描述了分子心脏病学学术生涯的五年培训计划。主要研究者在杜克大学医学中心完成了内科和心脏病学的临床培训，并被任命为杜克大学医学系教授，并获得医学副教授头衔。过去两年，首席研究员在 R. Sanders Williams 的实验室里接受了分子生物学和细胞生理学方面的研究培训。赞助商 R. Sanders Williams 博士成功指导了众多研究生、博士后研究员和心脏病专家，他们后来进入了学术医学领域。杜克大学心脏病学部也表现出了对年轻教师学术生涯发​​展的坚定承诺。 钙调神经磷酸酶是一种钙调节的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肌中的基因表达谱。 Homer 蛋白是支架蛋白家族，通过介导细胞表面蛋白与 SR/ER 上的受体（如 IP3 和兰尼碱受体）之间的相互作用，在钙信号转导中发挥关键作用。该项目的目标是确定 Homer 蛋白在调节钙调磷酸酶信号传导中的作用及其对肌肉重塑和心脏肥大的影响。具体目标如下： 1) 表征胚胎发育过程中横纹肌中 Homer 同工型表达的空间和时间模式以及对生理刺激的反应。 2) 确定 Homer 蛋白在组织培养模型中肌管发育和钙调磷酸酶信号传导中的作用。在这里，我们将评估我们的假设，即 Homer 同工型影响肌管发育、钙信号传导和钙调神经磷酸酶/NFAT 信号传导途径的激活。 3) 确定荷马亚型的过度表达和靶向破坏对小鼠模型中心脏和骨骼肌功能的影响。在这里，我们将使用功能获得/功能丧失策略来确定体内 Homer 蛋白在与纤维类型分化和心脏肥大相关的重塑事件中的作用。