Ese-1, a New Transcriptional Mediator of Inflammation

描述：(逐字)一个重要的未得到满足的医疗需求是有效的 治疗心血管疾病的炎症过程，炎症， 以及自身免疫性疾病。目前，这些疾病都是用药物治疗的 安全性不高且疗效有限的药物。只是最近 几类更具特异性的新型抗炎药 已经被释放了。我们的目标是确定炎症的哪些方面 由ETS转录因子Ese-L介导，其理念是 了解ESE-1在炎症中的作用可能最终导致 验证ESE-1作为重要的药物靶点。ESE-1之前曾被 涉及上皮特异性基因的调节，在正常情况下 生理条件下ESE-1的表达仅限于 上皮细胞谱系。我们现在提供强有力的证据来证明一种新奇的、意想不到的 ESE-1在炎症中的作用。令人惊讶的是，ESE-1在 类风湿关节炎患者滑膜在血管系统中的变化 内毒素血症，ESE-1的表达在几个 与炎症相关的细胞类型对炎症刺激的反应 如IL-1β、肿瘤坏死因子-α和内毒素。诱导ESE-1基因的表达 促炎刺激依赖于核因子-kB p50和p65的激活 通过高亲和力核因子-kB结合诱导ESE-L表达的家族成员 位于ESE-1启动子内。利用我们已经识别出的cDNA微阵列 作为ESE-1下游靶点的几个炎症反应基因包括 MMP1、MMP13、Fas、DR5、NOS-2、COX-2。促炎药的诱导作用 其中至少两个基因，NOS-2和COX-2的刺激在很大程度上依赖于 ESE-1诱导。因此，我们的假设是ESE-1是一种新的 在整体调控中起关键作用的炎症反应 一组炎症反应基因，并参与炎症过程 炎症性疾病。这项建议的目的是评估ESE的作用- 1炎症，使用小鼠慢性肉芽肿组织气囊 作为一种炎症模型的模型和微阵列分析 确定ESE-1调控的生物通路。因此，具体目标是： 具体目标#1.ESE-1是ESE-1的关键和直接调节因子吗？ 靶基因？ 具体目标2.炎性转录程序的哪一部分 ESE-1的表达？具体目标3：ESE-1在慢性炎症中起作用吗？ 阐明ESE-1在炎症中的作用将提供令人兴奋的 检验ESE-1是新的治疗靶点的假设的机会 用于抗炎药物开发。

DESCRIPTION: (Verbatim) One important unmet medical need is the effective treatment of inflammatory processes in cardiovascular disease, inflammation, and autoimmune diseases. At the moment these diseases are treated with drugs that have inadequate safety profiles and limited efficacy. Only recently several novel classes of anti-inflammatory drugs with a more specific profile have been released. Our goal is to determine which aspects of inflammation are mediated by the Ets transcription factor ESE-l, with the notion that understanding the role of ESE-1 in inflammation may ultimately lead to validation of ESE-1 as an important drug target. ESE-1 has previously been implicated in the regulation of epithelial-specific genes, and under normal physiological conditions ESE-1 expression is restricted to cells of the epithelial cell lineage. We now provide strong evidence for a novel, unexpected function for ESE-1 in inflammation. Strikingly, ESE-1 is expressed in the synovium of rheumatoid arthritis patients, in the vasculature during endotoxemia, and ESE-1 expression is rapidly and transiently induced in several cell types associated with inflammation in response to inflammatory stimuli such as IL-1beta, TNF-alpha, and endotoxin. Induction of ESE-1 expression by pro-inflammatory stimuli is dependent on activation of the NF-KB p50 and p65 family members which induce ESE-l expression via a high affinity NF-kB binding site within the ESE-1 promoter. Using cDNA microarrays we have identified several inflammation response genes as downstream targets for ESE- 1 including MMP-1, MMP-13, Fas, DR5, NOS-2, and COX-2. The induction by pro-inflammatory stimuli of at least two of these genes, NOS-2 and COX-2, depends heavily on ESE-1 induction. Thus, our hypothesis is that ESE-1 is a novel mediator of the inflammatory response that plays a critical role in the regulation of a whole set of inflammatory response genes and contributes to inflammatory processes in inflammatory diseases. The aim of this proposal is to evaluate the role of ESE- 1 in inflammation, using the murine chronic granulomatous tissue air pouch model as a model for one type of inflammation and microarray analysis to determine biological pathways regulated by ESE-1. Thus, the specific aims are: Specific Aim #1. Is ESE-1 a critical and direct regulator of ESE-1 inducible target genes? Specific Aim #2. Which part of the inflammatory transcriptional program is due to ESE-1 expression? Specific Aim #3. Does ESE-1 play a role in chronic inflammation? Elucidation of the function of ESE-1 in inflammation will provide exciting opportunities to test the hypothesis that ESE- 1 is a new therapeutic target for anti-inflammatory drug development.