REG OF SM22 ALPHA TRANSCRIPTION IN SMOOTH MUSCLE CELLS

描述（改编自研究者摘要）： 血管平滑肌细胞（SMC）的可塑性允许这种肌肉细胞 支持多种功能，包括维持动脉 通过收缩-舒张调节和通过增殖保持血管壁完整性 和细胞外基质的合成。 通过差异调节 SMC谱系特异性基因的不同表达，SMC可以调节 它们的表型从主要收缩型转变为主要合成型。 然而，在这方面， 目前对这一分子机制的了解相对较少 控制SMC特异性基因表达。 一种理解的方法是 调节SMC分化的分子机制是鉴定 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谱系限制 表达模式，我们使用小鼠SM 22 α基因作为模型 系统来检查控制SMC特异性基因表达的机制。 初步研究表明，SM 22 alpha是最早的 SMC谱系的发育标志物。 此外，280 bp的SM 22 alpha 启动子指导动脉SMC谱系限制性基因表达， 转基因小鼠 该转录调控元件包含 以前未描述的核蛋白结合位点， 谱系限制性反式作用因子。 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 SM 22 α基因在SMC中的表达。 拟议的研究旨在 阐明控制SMC特异性模式的分子机制 SM 22 α基因的表达。 这些研究的具体目标是：（一）确定 控制动脉SMC特异性的顺式作用元件 胚胎和出生后发育期间的SM 22 α启动子，（ii） 表征调节表达的反式作用因子， SM 22 α基因，（iii）检查活性的分子机制 对SM 22 α启动子活性的正、负调控因子， 和（iv）克隆并表征SMC特异性转录因子， 调节SM 22 α基因在SMC中的活性， 增加对SMC发育和分化的理解。 因此， 拟议的研究与了解 动脉粥样硬化和球囊血管成形术后再狭窄。

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.