Calcium and Gene Expression in Vascular Smooth Muscle

血管平滑肌中的钙和基因表达

基本信息

批准号：
7586739
负责人：
KAREN M LOUNSBURY
金额：
$ 34.2万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-03-05 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586739
关键词：
Abbreviations Affect Angiotensin II Animals Apoptosis Arteries Binding Binding Proteins Biological Biological Assay Biology Blood Vessels Calcium Calcium/calmodulin-dependent protein kinase Calmodulin Cardiovascular Diseases Cell Nucleus Cells Chromatin Communication Complex Cultured Cells Cyclic AMP Cyclic AMP Response Element Cyclic AMP-Responsive DNA-Binding Protein Cyclic GMP Cyclic Nucleotides Cyclin D1 Cytoplasm DUSP1 gene Development Experimental Designs Extracellular Signal Regulated Kinases Figs - dietary Fluorescent Antibody Technique Gene Expression Gene Targeting Genes Genetic Transcription Genomics Grant Growth Growth Factor Hyperactive behavior Hypertension Hypertrophy Image Immigration Immunology procedure In Situ Individual Injury Inositol Laboratory Study Lead Life Long-Term Effects MAPK phosphatase MEKs Mediating Methods Mitogen Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modeling Molecular Molecular Biology Muscle function Nuclear PDGFRB gene Pathology Pathway interactions Pattern Phospholipase C Phosphorylation Phosphotransferases Physiological Plasmids Plasminogen Activator Inhibitor 1 Platelet-Derived Growth Factor Play Prevention strategy Protein Binding Proteins Receptor, Angiotensin, Type 1 Recovery Regulation Relative (related person)Research Research Personnel Role Serum Response Element Serum Response Factor Signal Pathway Signal Transduction Site-Directed Mutagenesis Smooth Muscle Smooth Muscle Myocytes Son of Sevenless Proteins Source Stimulus Stroke Techniques Testing Time Transcription Factor AP-1 Transcriptional Activation Transfection Translations Vascular Smooth Muscle cardiovascular disorder prevention cerebral artery cerebrovascular in vivo Model inorganic phosphate migration novel osteopontin programs promoter protein activation protein protein interaction research study response sensor transcription factor transmission process vascular smooth muscle cell migration vascular smooth muscle cell proliferation voltage voltage gated channel

项目摘要

DESCRIPTION (provided by applicant): The proliferative response of vascular smooth muscle cells (VSMCs) plays a key role in the recovery of arteries from injury and the development of cardiovascular diseases. The broad long-term objective of this research is to understand pathways important for transmission of proliferative signals from the cytoplasm to the nuclear transcription machinery in VSMCs. A relationship between Ca2+ and proliferation has been implicated, but the mechanisms have not been identified. In addition, whereas transmission of Ca2+ and mitogenic signals is necessary to elicit specific changes in gene expression, the communication between these pathways in the cytoplasm and nucleus is not known. The specific aims of this proposal explore a novel mechanism for Ca2+-mediated gene transcription in smooth muscle in which distinct sources of Ca2+ interact with extracellular signal-regulated kinase (ERK) signals to elicit specific transcriptional programs that are necessary for the development of hypertension-induced pathologies. Previous studies by this laboratory group have shown that different sources of Ca2+ lead to the activation of the Ca2+/cAMP response element binding protein (CREB) resulting in transcription of selective gene targets. The specific aims of this proposal explore the molecular mechanisms of these findings by 1) Exploring the connection between specific Ca2+ signals and kinase activation that determine selective gene expression in VSMCs; 2) Identifying factors that interact with CRE-containing promoters in response to Ca2+ signals; and 3) Defining a role for CREB and ERK signaling in gene transcription that modulates hypertension-induced proliferation and migration of VSMCs. To achieve these aims, the proposed experiments will use live-cell Ca2+ imaging, kinase assays, immunologic assays, chromatin analysis, promoter/transcription analysis, cell and intact artery transfection, and an in vivo model of hypertension. The research personnel have expertise in cell signaling, vascular biology, and Ca2+ dynamics. The integrated experimental design, which combines cultured cell and intact artery approaches, will drive support for new paradigms in Ca2+-regulated gene transcription and the results of these experiments have the potential to identify new targets for reducing vascular pathologies associated with VSMC proliferation.

描述（由申请人提供）：血管平滑肌细胞（VSMC）的增殖反应在损伤中恢复动脉和心血管疾病的发展中起关键作用。这项研究的广泛长期目标是了解对于将增殖信号从细胞质传播到VSMC中的核转录机制很重要的途径。 CA2+与增殖之间的关系已涉及，但尚未确定这些机制。另外，尽管Ca2+和有丝分裂信号的传播对于引起基因表达的特定变化是必需的，但这些途径在细胞质和核中的通信尚不清楚。该提案的具体目的探索了平滑肌中Ca2+介导的基因转录的新机制，在这种机制中，Ca2+的不同来源与细胞外信号调节激酶（ERK）信号相互作用，以引起特定的转录程序，这对于发展高血压诱导的病理学所必需。该实验室组的先前研究表明，CA2+的不同来源导致Ca2+/CAMP响应元件结合蛋白（CREB）的激活，从而导致选择性基因靶标的转录。该提案的具体目的通过1）探索确定VSMC中选择性基因表达的特定CA2+信号和激酶激活之间的联系； 2）识别与CA2+信号响应含有CRE的启动子相互作用的因素； 3）定义CREB和ERK信号传导在基因转录中的作用，该基因转录调节高血压诱导的VSMC的增殖和迁移。为了实现这些目标，提出的实验将使用活细胞Ca2+成像，激酶测定，免疫学分析，染色质分析，启动子/转录分析，细胞和完整的动脉转染以及体内高血压模型。研究人员在细胞信号，血管生物学和CA2+动力学方面具有专业知识。结合培养的细胞和完整动脉方法的综合实验设计将推动对Ca2+调节基因转录中新范式的支持，并且这些实验的结果有可能确定减少与VSMC增殖相关的血管病理的新靶标。