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（由申请方提供）：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。已知Ca 2+信号调节细胞增殖和运动性，尽管这一知识尚未很好地整合到分子模型中，部分原因是缺乏对Ca 2+依赖性效应机制和靶点的了解。这项资助正在进行的工作集中在一个主要的Ca 2+信号效应器，即多功能Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）的结构和功能。VSM细胞迁移和增殖是“合成表型”细胞的特性，这些细胞尚未获得或失去分化的收缩蛋白标记物和功能。在分化的收缩和增殖/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，但尚未完全理解。一个新兴的概念，从过去的资助期的结果一致，是疾病或损伤诱导的Ca 2+信号传导机制和动力学的变化有助于发展的迁移/增殖VSM表型促进血管壁重塑。这一更新的总体目标是测试的概念，钙信号通过特定的CaMKII亚型，调节VSM基因转录，是VSM表型的决定因素。这一概念将通过追求三个目标来检验：1。我们将测试CaMK II调节合成表型VSM中的共阻遏物HDAC 4和HDAC 5的假设。转录激活因子MEF 2将作为影响基因转录的CaMKII/HDAC 4，5依赖性靶点进行测试。测试CaMKII同种型与该调节途径偶联的特异性。2.）的情况。将评估CaMK II同工酶作为VSM中转录抑制因子REST/NRSF表达和活性的调节剂的功能，并将HDAC 4/5作为中间体进行测试。3.）第三章将使用球囊损伤的大鼠颈动脉作为模型在体内评价HDAC 4/5和REST的CaMK II依赖性调节在调节VSM表型和血管重塑中的功能。通过阐明CaMKII亚型调节对血管损伤的反应的功能后果，这些研究的结果有望提供对VSM细胞表型调节的潜在机制以及Ca 2+信号和显著的Ca 2+依赖性多功能蛋白激酶调节VSM细胞功能并导致血管疾病的机制的见解。公共卫生相关性：血管平滑肌（VSM）细胞增殖和迁移与病理学事件有关，例如动脉粥样硬化、癌症血管生成和与再狭窄或移植血管病变有关的内膜增生，所有这些都在西方社会普遍存在。通过阐明CaMKII异构体在调节转录抑制因子、IIa类HDAC和REST中的机制和功能后果，我们期望获得对Ca 2+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提供新的靶点。