Calcium/Calmodulin Activated Kinases in Smooth Muscle

平滑肌中钙/钙调蛋白激活的激酶

• 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
• 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

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）细胞的迁移和增殖在发育过程中发生，伤口 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性，尽管这些知识尚未很好地整合到分子中 模型，部分原因是缺乏对Ca2+依赖性效应器机制和目标的见解。正在进行的工作 由这笔赠款资助的重点是一个主要的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 失去了分化的收缩蛋白标记和功能。 VSM表型调制 分化的收缩和增殖/迁徙状态具有相当大的兴趣和临床重要性， 但不完全理解。一个与过去资金期结果一致的新兴概念是 疾病或受伤引起的Ca2+信号传导机制和动力学的变化有助于 迁移/增殖的VSM表型的发展，促进血管壁重塑。总体 该更新的目的是测试通过特定CAMKII同工型通过CA2+信号传导的概念，调节VSM 基因转录，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。）我们将测试CAMKII调节的假设 合成表型VSM中的共抑制剂HDAC4和HDAC5。转录激活器MEF2将是 以CAMKII/HDAC4,5依赖性靶靶标测试，影响基因转录。 CAMKII同工型特异性 测试与该调节途径的耦合。 2.）CAMKII同工酶作为调节剂的功能 将评估转录抑制器ret/nrsf的表达和VSM中的活性，HDAC4/5将是 被测试为中介。 3.）CAMKII依赖性调节HDAC4/5的功能，并在调节中休息 VSM表型和血管重塑将在体内使用气球损伤的大鼠颈动脉评估 作为模型。 通过阐明响应血管损伤的CAMKII同工型调节的功能后果， 这些研究的结果有望提供对表型基础机制的见解 VSM单元和机制的调制，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，并导致血管疾病。