Store Operated Calcium Channels Function in Vascular Smooth Muscle

血管平滑肌中存储操纵的钙通道功能

基本信息

批准号：
8005340
负责人：
Salvatore Mancarella
金额：
$ 5.05万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8005340
关键词：
Animals Blood Vessels Calcineurin Calcium Calcium Channel Cell Proliferation Disease Dominant-Negative Mutation Electrophysiology (science)Functional disorder Gene Expression Growth Life Mediating Mus Myopathy NFAT Pathway Pathway interactions Phenotype Physiological Physiology Play Process Proteins Regulation Role STIM1 gene Signal Transduction Smooth Muscle Smooth Muscle Myocytes Testing Therapeutic Vascular Smooth Muscle Work cellular imaging insight novel prevent public health relevance response spatiotemporal vascular smooth muscle cell proliferation

Animals Blood Vessels Calcineurin Calcium Calcium Channel Cell Proliferation Disease Dominant-Negative Mutation Electrophysiology (science)Functional disorder Gene Expression Growth Life Mediating Mus Myopathy NFAT Pathway Pathway interactions Phenotype Physiological Physiology Play Process Proteins Regulation Role STIM1 gene Signal Transduction Smooth Muscle Smooth Muscle Myocytes Testing Therapeutic Vascular Smooth Muscle Work cellular imaging insight novel prevent public health relevance response spatiotemporal vascular smooth muscle cell proliferation

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项目摘要

DESCRIPTION (provided by applicant): The project aims to understand how unique signatures of Ca2+ mediated by STIM proteins control the proliferation of vascular smooth muscle cells (VSMC). Ca2+ signals play a crucial role in not only controlling vascular contraction but also in regulating the growth and proliferation of smooth muscle cells. The work examines the function of two crucial proteins, STIM1 and STIM2, that sense changes in the Ca2+ within the SR lumen of VSMCS, and through a highly coordinated translocation process, move into small specialized junctions between the SR and PM. STIM proteins directly activate Ca2+ channels in the PM and hence control Ca2+ entry into VSMCS. The project has two specific aims: Aim 1: To examine the distinct functional roles of STIM1 and STIM2 proteins in mediating Ca2+ signals in VSMCs. These studies will test the hypothesis that the STIM2 phenotype in VSMCs from SM-STIM1-KO animals has a "Ca2+ signature response" important in mediating distinct physiological differences in VSMC proliferation. The experimental approach to test this hypothesis utilizes a combination of live cellular imaging, expression of dominant negative channel proteins, electrophysiology, and novel Ca2+ probes to assess the functional roles of STIM-mediated Ca2+ signals in VSMCs and examines: (a) the "temporal Ca2+ signature" of Ca2+ signals in VSMCs from SM-STIM1- KO mice; (b) the "spatial Ca2+ signature" of Ca2+ signals in VSMCs from SM-STIM1-KO mice; and (c) how luminal SR levels reflect the STIM-mediated Ca2+ signature in VSMCs. Aim 2: To determine how STIM-induced Ca2+ signature responses regulate proliferative pathways in VSMCs. The hypothesis to be tested is that STIM-specific Ca2+ entry signals control gene expression and proliferative VSMC responses through the calcineurin/NFAT axis. The aims are to determine (a) how STIM proteins control expression of components of the calcineurin NFAT pathway in proliferative VSMC; (b) STIM-mediated Ca2+ signaling occurs during mitogenic stimulation; (c) how STIM proteins control the NFAT translocation/gene expression pathway.

描述（由申请人提供）：该项目旨在了解刺激蛋白介导的Ca2+独特特征如何控制血管平滑肌细胞的增殖（VSMC）。 CA2+信号不仅在控制血管收缩，而且在调节平滑肌细胞的生长和增殖方面起着至关重要的作用。该作品研究了两种至关重要的蛋白STIM1和STIM2的功能，这些蛋白质在VSMC的SR腔内以及通过高度协调的易位过程中的Ca2+变化，进入了SR和PM之间的小型专业连接。刺激蛋白直接激活PM中的Ca2+通道，因此控制Ca2+进入VSMC。该项目具有两个具体的目的：目标1：检查stim1和stim2蛋白在VSMC中介导的Ca2+信号中的独特功能作用。这些研究将检验以下假设：SM-stim1-KO动物VSMC中的STIM2表型对于介导VSMC增殖的不同生理差异的“ Ca2+签名响应”重要。 The experimental approach to test this hypothesis utilizes a combination of live cellular imaging, expression of dominant negative channel proteins, electrophysiology, and novel Ca2+ probes to assess the functional roles of STIM-mediated Ca2+ signals in VSMCs and examines: (a) the "temporal Ca2+ signature" of Ca2+ signals in VSMCs from SM-STIM1- KO mice; （b）来自SM-stim1-KO小鼠的VSMC中Ca2+信号的“空间Ca2+签名”；（c）腔SR水平如何反映VSMC中刺激的Ca2+特征。目标2：确定刺激诱导的Ca2+特征反应如何调节VSMC中的增殖途径。要检验的假设是，刺激特异性的Ca2+进入信号通过钙调神经酶/NFAT轴控制基因表达和增殖VSMC响应。目的是确定（a）刺激蛋白如何控制增生性VSMC中钙调神经素NFAT途径成分的表达；（b）在有丝分裂刺激期间发生刺激介导的Ca2+信号传导；（c）刺激蛋白如何控制NFAT易位/基因表达途径。