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：
7822181
负责人：
HAROLD A SINGER
金额：
$ 1.57万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822181
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 Proliferation 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 public health relevance response restenosis vascular smooth muscle cell migration vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: vascular smooth muscle (VSM) cell proliferation and migration is associated with pathological events such as atherosclerosis, cancer angiogenesis, and intimal hyperplasia associated with restenosis or transplant vasculopathy, all prevalent in Western society. By elucidating the mechanisms and functional consequences of CaMKII isoforms in regulating the transcriptional repressors, class IIa HDACs and REST, we expect to gain new insights into mechanisms by which Ca2+ signals modulate VSM cell phenotype and function. Knowledge of these mechanisms could provide new targets for therapeutics aimed at controlling vascular disease and restenosis.

描述（由申请人提供）：血管平滑肌（VSM）细胞的迁移和增殖发生在发育，伤口愈合，血管生成，并有助于血管疾病的发展。已知CA2+信号可以调节细胞增殖和运动，尽管这些知识尚未很好地整合到分子模型中，部分原因是缺乏对Ca2+依赖性效应器机制和靶标的见解。该赠款资助的正在进行的工作集中在一个主要的Ca2+信号效应子的结构和功能上，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或丢失的分化收缩蛋白标记和功能的“合成表型”细胞的特性。分化收缩和增殖/迁移状态之间的VSM表型调节具有相当大的兴趣和临床重要性，但尚不完全理解。与过去融资期的结果一致的一个新兴概念是，疾病或受伤引起的CA2+信号传导机制的变化和动力学有助于迁移/增殖的VSM表型的发展，促进血管壁重塑。该更新的总体目的是测试通过特定CAMKII同工型Ca2+信号传导调节VSM基因转录的概念，并且是VSM表型的决定因素。该概念将通过追求三个目标来测试：1。）我们将在合成表型VSM中调节CAMKII调节共抑制剂HDAC4和HDAC5的假设。转录激活剂MEF2将被测试为CAMKII/HDAC4,5依赖性靶标，影响基因转录。测试与该调节途径的耦合中的CAMKII同工型特异性。 2.）CAMKII同工酶作为转录阻遏物REST/NRSF表达和VSM中活性的调节剂的功能将进行评估，HDAC4/5将作为中间体进行测试。 3.）使用气球受损害的大鼠颈动脉作为模型，将在体内评估CAMKII依赖性调节HDAC4/5和在调节VSM表型和血管重塑中的休息。通过阐明CaMKII同工型调节对血管损伤的功能后果，这些研究的结果有望提供对VSM细胞的表型调节的基础机制的见解，而CA2+信号+ CA2+信号和明显的CA2+依赖性依赖于依赖的多函数蛋白蛋白Kinase vastem vastem vasts vssm vastem vestult vestultion veat conconution consutions wonquins and Conconution conconution conconution conconution。公共卫生相关性：血管平滑肌（VSM）细胞的增殖和迁移与病理事件有关，例如动脉粥样硬化，癌症血管生成和与再狭窄或移植的血管病相关的内膜增生，在西方社会中都普遍。通过阐明CAMKII同工型在调节转录阻遏物，IIA级HDAC和REST时的机制和功能后果，我们希望获得对CA2+信号调节VSM细胞表型和功能的机制的新见解。这些机制的知识可以为旨在控制血管疾病和再狭窄的治疗剂提供新的靶标。