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: 2901263
• 负责人: Michael S Parmacek
• 金额: $ 22.24万
• 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/2901263
• 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（根据研究者的摘要改编）：表型 血管平滑肌细胞（SMC）的可塑性允许这种肌肉细胞 谱系来维护各种功能，包括维持动脉 通过收缩松弛和血管壁的完整性通过增殖来进行音调 和细胞外基质的合成。 通过差异调节 SMC特异性基因的不同集合的表达，SMC可以调节 它们的表型从主要是收缩到主要合成的。 然而， 目前对分子机制的了解相对较少 该控制SMC特异性基因表达。 一种理解的方法 调节SMC分化的分子机制是确定 并表征顺式作用序列和跨性因素 控制SMC特异性转录。 由于其SMC谱系限制 表达模式，我们已经使用鼠SM22Alpha基因作为模型 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血统的发展标记。 此外，280 bp SM22Alpha 启动子指导动脉SMC谱系限制基因表达 转基因小鼠。 此转录调节元件包含 以前未描述的核蛋白结合位点 谱系限制的跨力因素。 这些数据支持假设 那种新型的SMC谱系限制转录因子控制 Sm22alpha基因在SMC中的表达。 拟议的研究是设计的 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：（i）确定 控制动脉SMC特异性活动的顺式作用元素 胚胎和产后发育过程中的SM22Alpha启动子（II） 表征调节表达表达的跨性别因子 SM22Alpha基因（III）检查了分子机制 SM22Alpha启动子活性的正和负调控因素， （iv）克隆并表征了SMC特异性转录因子 调节SM22alpha基因在SMC中的活性应从根本上 增加对SMC发展和分化的理解。 因此， 提出的研究与了解的发病机理有关 气球血管成形术后动脉粥样硬化和再狭窄。