Regulation of Vascular Inflammation by ESE-1

描述（申请人摘要）：炎症，动脉粥样硬化的标志 和其他血管疾病，其特征在于激活几个 基因包括细胞因子、粘附分子、环加氧酶和一氧化氮合酶， 氧化物合酶这些研究的长期目标是确定关键的 血管生成和增殖所需的决定因素 炎症我们的方法来解开潜在的分子机制 血管炎症是为了确定转录因子， 这些回应。已知转录因子的NF-κ B家族是 这些事件的关键媒介。我们发现了一种新的外星人 一种转录因子ESE- 1，响应于白细胞介素-1而被诱导 血管平滑肌中的β、肿瘤坏死因子α和内毒素 细胞、内皮细胞和单核细胞。这种归纳至少在一定程度上 由NF-κ B介导。ESE-1在Ets因子中是独特的，因为它具有两个 在HMG中发现的DNA结合结构域、经典Ets结构域和A/T钩结构域 proteins.我们的研究结果表明，ESE-1的两个DNA结合结构域可以 与NF-κ B的p50亚基结合。我们已经确定了诱导型 一氧化氮合酶（NOS 2）作为ESE-I的靶标。ESE-1是一种强大的 NOS 2基因启动子的反式激活因子和ESE-1导入细胞 可以激活NOS 2基因的表达。在大鼠内毒素血症模型中， 在急性血管炎症中，ESE- 1在血管平滑肌中被强烈诱导， 肌肉细胞和内皮细胞。这些研究的假设是， Ets因子ESE-1是血管炎症的转录介质。 这项研究的具体目标是： I.定义ESE-1作为转录激活因子的生物学作用， NOS 2基因和其他与血管炎症相关的基因。 二.确定DNA结合特异性和功能的重要性， 两个ESE-1 DNA结合结构域。 三.确定ESE-1表达对血管细胞的生物学效应 功能 用于实现这些目标的方法和模型包括电泳 迁移率变动分析，免疫组织化学，转录谱，动物 血管炎症模型和转基因模型。的结果予以 研究应该提供新的见解的分子机制参与 调节血管炎症并提供潜在的新治疗途径 用于治疗血管疾病，例如动脉粥样硬化、再狭窄和 与移植相关的血管病变。

DESCRIPTION (Applicant's abstract): Inflammation, a hallmark of atherosclerosis and other vascular diseases, is characterized by the activation of several genes including cytokines, adhesion molecules, cyclooxygenases, and nitric oxide synthase. The long term goal of these studies is to identify the critical determinants required for the initiation and propagation of vascular inflammation. Our approach to unraveling the molecular mechanisms underlying vascular inflammation is to identify the transcription factors that regulate these responses. The NF-kappa B family of transcription factors are known to be critical mediators of these events. We have identified a novel Ets transcription factor ESE- 1, that is induced in response to interleukin- 1 beta, tumor necrosis factor alpha, and endotoxin in vascular smooth muscle cells, endothelial cells and monocytes. This induction is at least in part mediated by NF-kappa B. ESE-1 is unique among Ets factors in that it has two DNA binding domains, a classical Ets domain and an A/T hook domain found in HMG proteins. Our results demonstrate that both DNA binding domains of ESE-1 can bind to the p50 subunit of NF-kappa B. We have identified the inducible form of nitric oxide synthase (NOS2) as a target for ESE-l. ESE-1 is a strong transactivator of the NOS2 gene promoter and introduction of ESE-1 into cells can activate NOS2 gene expression. In a rat model of endotoxemia associated with acute vascular inflammation, ESE- 1 is strongly induced in vascular smooth muscle cells and endothelial cells. The hypothesis for these studies is that the Ets factor ESE-1 is a transcriptional mediator of vascular inflammation. The specific aims of the study are to: I. Define the biological role of ESE-1 as a transcriptional activator of the NOS2 gene and other genes associated with vascular inflammation. II. Determine the DNA binding specificity and the functional importance of the two ESE-1 DNA binding domains. III. Determine the biological effect of ESE-1 expression on vascular cell function. The methods and models used to achieve these goals include electrophoretic mobility shift assays, immunohistochemistry, transcriptional profiling, animal models of vascular inflammation, and transgenic models. The results of these studies should provide new insights into the molecular mechanisms involved in regulating vascular inflammation and provide potential new therapeutic avenues for treatment of vascular diseases such as atherosclerosis, restenosis, and the vasculopathy associated with transplantation.