REG OF SM22 ALPHA TRANSCRIPTION IN SMOOTH MUSCLE CELLS

平滑肌细胞中 SM22 α 转录的调节

• 批准号: 6183772
• 负责人: Michael S Parmacek
• 金额: $ 24.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183772
• 关键词: cell differentiation; developmental genetics; gene expression; genetic regulation; genetic regulatory element; genetically modified animals; laboratory mouse; tissue /cell culture; transcription factor; vascular smooth muscle

DESCRIPTION (Adapted from Investigator's Abstract): The phenotypic plasticity of vascular smooth muscle cells (SMCs) permits this muscle cell lineage to subserve diverse functions including the maintenance of arterial tone via contraction- relaxation and vessel wall integrity by proliferation and synthesis of extracellular matrix. By differentially regulating the expression of distinct sets of SMC lineage-specific genes, SMCs can modulate their phenotype from primarily contractile to primarily synthetic. However, relatively little is currently understood about the molecular mechanisms that control SMC-specific gene expression. One approach to understanding the molecular mechanisms that regulate SMC differentiation is to identify and characterize the cis-acting sequences and trans-acting factors that control SMC-specific transcription. Because of its SMC lineage-restricted pattern of expression, we have used the murine SM22alpha gene as a model system to examine the mechanisms that control SMC-specific gene expression. Preliminary studies demonstrated that SM22alpha is one of the earliest developmental markers of the SMC lineage. Moreover, the 280-bp SM22alpha promoter directs arterial SMC lineage-restricted gene expression in transgenic mice. This transcriptional regulatory element contains previously undescribed nuclear protein binding sites that bind lineage-restricted trans-acting factors. These data support the hypothesis that novel SMC lineage- restricted transcription factors control the expression of the SM22alpha gene in SMCs. The proposed studies are designed to elucidate the molecular mechanisms that control the SMC-specific pattern of SM22alpha gene. The specific aims of these studies are to: (i) identify the cis-acting elements that control activity for the arterial SMC-specific SM22alpha promoter during embryonic and postnatal development, (ii) characterize the trans-acting factors that regulate expression of the SM22alpha gene, (iii) examine the molecular mechanisms underlying activity of positive and negative regulatory factors on SM22alpha promoter activity, and (iv) clone and characterize SMC-specific transcription factors that regulate activity of the SM22alpha gene in SMCs should fundamentally increase understanding of SMC development and differentiation. As such, the proposed studies are relevant to understanding the pathogenesis of atherosclerosis and restenosis following balloon angioplasty.

描述(改编自《调查者摘要》)：表型 血管平滑肌细胞(SMCs)的可塑性允许这种肌肉细胞 世系服务于不同的功能，包括维持动脉 收缩-松弛带来的音调和增殖带来的管壁完整性 细胞外基质的合成。通过差异化地监管 不同的SMC谱系特异性基因的表达，SMC可以调节 它们的表型从主要收缩到主要合成。然而， 目前对分子机制的了解相对较少。 控制SMC特异性基因表达的基因。一种理解的方法 调控SMC分化的分子机制是识别 并表征顺式作用序列和反式作用因子 控制SMC特异性转录。由于其SMC血统受限 表达模式，我们用小鼠SM22Alpha基因作为模型 系统，以检查控制SMC特异性基因表达的机制。 初步研究表明，SM22Alpha是最早的 SMC谱系的发育标记物。此外，280-BP的SM22Alpha 启动子调控动脉系膜细胞系限制基因表达 转基因小鼠。这种转录调控元件包含 以前未描述的结合核蛋白的结合部位 血统限制的反式作用因子。这些数据支持这一假设 新的SMC谱系限制性转录因子控制着 SM22α基因在血管内皮细胞中的表达建议的研究是设计的 阐明控制SMC特异性模式的分子机制 SM22Alpha基因。这些研究的具体目的是：(1)确定 控制动脉SMC特异性活性的顺式作用元件 SM22α启动子在胚胎和出生后发育中的作用(II) 描述调节基因表达的反式作用因子的特征 SM22pha基因，(Iii)研究活性的分子机制 对SM22α启动子活性的正负调控因子， 以及(Iv)克隆和鉴定SMC特异性转录因子 从根本上调控SM22α基因在SMC中的活性 增加对SMC发展和分化的了解。因此， 建议的研究与理解糖尿病的发病机制有关。 动脉粥样硬化和球囊血管成形术后的再狭窄。