Calcium/Calmodulin Activated Kinases in Smooth Muscle

平滑肌中钙/钙调蛋白激活的激酶

• 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
• 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

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、血管生成过程中，并有助于血管疾病的进展。众所周知，Ca2+信号调节细胞增殖和运动，尽管这方面的知识还没有很好地整合到分子模型中，部分原因是缺乏对Ca2+依赖效应机制和靶点的了解。由该基金资助的正在进行的工作主要集中在一个主要的Ca2+信号效应器的结构和功能上，即多功能Ca2+/钙调素依赖性蛋白激酶II （CaMKII）。VSM细胞迁移和增殖是“合成表型”细胞的特性，这些细胞没有获得或失去分化的收缩蛋白标记物和功能。不同收缩状态和增殖/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，但尚未完全了解。一个新兴的概念，与过去资助期的结果一致，是疾病或损伤引起的Ca2+信号机制和动力学的变化有助于迁移/增殖性VSM表型的发展，促进血管壁重塑。这项更新的总体目标是测试Ca2+信号通过特定CaMKII亚型调节VSM基因转录和VSM表型决定因素的概念。这个概念将通过追求三个目标来检验：我们将验证CaMKII在合成表型VSM中调控共抑制因子HDAC4和HDAC5的假设。转录激活子MEF2将作为影响基因转录的CaMKII/ hdac4,5依赖性靶标进行测试。CaMKII异构体与这一调控途径偶联的特异性有待检验。2.） 我们将评估CaMKII同工酶作为VSM中转录抑制因子REST/NRSF表达和活性的调节因子的功能，并测试HDAC4/5作为中介。3)。我们将以球囊损伤大鼠颈动脉为模型，在体内评估camkii依赖性调控HDAC4/5和REST在调节VSM表型和血管重构中的作用。通过阐明CaMKII异构体调节对血管损伤的功能后果，这些研究结果有望提供对VSM细胞表型调节机制的见解，以及Ca2+信号和突出的Ca2+依赖性多功能蛋白激酶调节VSM细胞功能和促进血管疾病的机制。公共卫生相关性：血管平滑肌（VSM）细胞增殖和迁移与病理事件相关，如动脉粥样硬化、癌症血管生成和与再狭窄或移植血管病变相关的内膜增生，这些都在西方社会普遍存在。通过阐明CaMKII亚型在调节转录抑制因子IIa类hdac和REST中的机制和功能后果，我们期望获得Ca2+信号调节VSM细胞表型和功能的机制的新见解。了解这些机制可以为控制血管疾病和再狭窄的治疗提供新的靶点。