Calcium/Calmodulin Activated Kinases in Smooth Muscle

平滑肌中钙/钙调蛋白激活的激酶

基本信息

批准号：
8449739
负责人：
HAROLD A SINGER
金额：
$ 36.99万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8449739
关键词：
Affect Atherosclerosis Balloon Angioplasty Biological Assay Blood Vessels Calcium Calcium-Activated Potassium Channel Calmodulin Cardiac Myocytes Carotid Arteries Carotid Artery Injuries Cations Cell Proliferation Cell physiology Cells Clinical Complex Contractile Proteins Coupling Data Development Disease Event Funding Gene Expression Genes Genetic Transcription Goals Grant HDAC4 gene HDAC5 gene Histones Hyperplasia In Vitro Injury Isoenzymes Knowledge Link Luciferases Malignant Neoplasms Mediator of activation protein Modeling Molecular Molecular Models Pathway interactions Phenotype Phosphorylation Phosphotransferases Physiological Process Property Protein Isoforms Protein Kinase Publishing Rattus Reagent Regulation Regulatory Pathway Reporting Signal Transduction Smooth Muscle Smooth Muscle Myocytes Societies Specificity Stimulus Structure Testing Transcription Coactivator Transcription Repressor/Corepressor Transplantation Vascular Diseases Vascular Smooth Muscle Vascular remodeling Work Wound Healing angiogenesis base calmodulin-dependent protein kinase II cell motility in vivo injured insight interest migration molecular modeling neointima formation new therapeutic target novel nucleocytoplasmic transport promoter response restenosis vascular smooth muscle cell migration vascular smooth muscle cell proliferation

项目摘要

Migration and proliferation of vascular smooth muscle (VSM) cells occurs during development, wound healing, angiogenesis, and contributes to the progression of vascular disease. Ca2+ signals are known to regulate cell proliferation and motility, although this knowledge has not been well integrated into molecular models, due in part to lack of insight into Ca2+-dependent effector mechanisms and targets. Ongoing work funded by this grant has focused on the structure and function of one major Ca2+ signal effector, namely multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII). VSM cell migration and proliferation are properties of "synthetic phenotype" cells that have not acquired, or have lost, differentiated contractile protein markers and function. VSM phenotype modulation between differentiated contractile and proliferative/migratory states are of considerable interest and clinical importance, but are incompletely understood. An emerging concept, consistent with results from the past funding period, is that disease- or injury-induced changes in Ca2+ signaling mechanisms and dynamics contributes to development of the migratory/proliferative VSM phenotype promoting vascular wall remodeling. The overall objective of this renewal is to test the concept that Ca2+ signaling via specific CaMKII isoforms, regulates VSM gene transcription and is a determinant of VSM phenotype. This concept will be tested by pursuing three aims: 1.) We will test the hypothesis that CaMKII regulates the co-repressors HDAC4 and HDAC5 in synthetic phenotype VSM. The transcription activator MEF2 will be tested as a CaMKII/HDAC4,5-dependent target affecting gene transcription. CaMKII isoform specificity in coupling to this regulatory pathway be tested. 2.) The function of CaMKII isozymes as regulators of the transcriptional repressor REST/NRSF expression and activity in VSM will be evaluated and HDAC4/5 will be tested as intermediaries. 3.) The function of CaMKII-dependent regulation of HDAC4/5 and REST in regulating VSM phenotype and vascular remodeling will be evaluated in vivo using the balloon-injured rat carotid artery as a model. By elucidating the functional consequences of CaMKII isoform modulation in response to vascular injury, the results of these studies are expected to provide insights into mechanisms underlying phenotypic modulation of VSM cells and mechanism(s) by which Ca2+ signals and a prominent Ca2+-dependent multifunctional protein kinase modulates VSM cell function and contributes to vascular disease.

血管平滑肌 (VSM) 细胞在发育、伤口过程中发生迁移和增殖愈合、血管生成，并有助于血管疾病的进展。 Ca2+ 信号已知调节细胞增殖和运动，尽管这一知识尚未很好地整合到分子中模型，部分原因是缺乏对 Ca2+ 依赖性效应机制和靶点的了解。正在进行的工作该拨款资助的重点是一个主要 Ca2+ 信号效应器的结构和功能，即多功能 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII)。 VSM细胞迁移和增殖是尚未获得的“合成表型”细胞的特性，或者失去了分化的收缩蛋白标记和功能。 VSM表型调制之间分化的收缩状态和增殖/迁移状态具有相当大的兴趣和临床重要性，但并不完全理解。与过去资助期的结果一致的一个新兴概念是疾病或损伤引起的 Ca2+ 信号传导机制和动力学变化有助于迁移/增殖 VSM 表型的发展促进血管壁重塑。整体此次更新的目的是测试 Ca2+ 信号通过特定 CaMKII 亚型调节 VSM 的概念基因转录，是 VSM 表型的决定因素。这个概念将通过追求三个目标来检验：1.）我们将检验 CaMKII 调节的假设合成表型 VSM 中的共阻遏物 HDAC4 和 HDAC5。转录激活子 MEF2 将是作为影响基因转录的 CaMKII/HDAC4,5 依赖性靶标进行测试。 CaMKII 亚型特异性与该调节途径的耦合进行测试。 2.) CaMKII 同工酶作为调节剂的功能将评估 VSM 中的转录阻遏蛋白 REST/NRSF 表达和活性，并评估 HDAC4/5 作为中介进行测试。 3.) HDAC4/5 和 REST 的 CaMKII 依赖性调节功能将使用球囊损伤的大鼠颈动脉在体内评估 VSM 表型和血管重塑作为模特。通过阐明 CaMKII 异构体调节对血管损伤的功能影响，这些研究的结果预计将提供对表型潜在机制的见解 VSM 细胞的调节和 Ca2+ 信号传导的机制以及显着的 Ca2+ 依赖性多功能蛋白激酶调节 VSM 细胞功能并导致血管疾病。