Ese-1, a New Transcriptional Mediator of Inflammation

Ese-1，一种新的炎症转录介质

• 批准号: 6873688
• 负责人: TOWIA A. LIBERMANN
• 金额: $ 34万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6873688
• 关键词: CD95 molecule; binding sites; chronic granulomatous disease; cytokine; disease /disorder model; fibroblasts; gene induction /repression; gene mutation; genetic regulatory element; inflammation; keratinocyte; laboratory mouse; macrophage; metalloendopeptidases; microarray technology; molecular pathology; monocyte; protein binding; tissue /cell culture; transcription factor; transfection; vascular endothelium

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.

描述：（逐字）一个重要的未满足的医疗需求是有效的 治疗心血管疾病，炎症， 和自身免疫性疾病。目前这些疾病都是用药物治疗的 安全性不足且疗效有限。最近才 几种新的抗炎药物具有更具体的概况 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-I介导，其概念是， 了解ESE-1在炎症中的作用可能最终导致 确认ESE-1作为重要的药物靶点。ESE-1以前是 参与上皮特异性基因的调节，在正常情况下， 在生理条件下，ESE-1的表达仅限于 上皮细胞系我们现在为一个新奇的，意想不到的 ESE-1在炎症中的作用。引人注目的是，ESE-1表达于 类风湿性关节炎患者的滑膜， 内毒素血症，ESE-1表达是快速和短暂诱导，在几个 与炎症相关的细胞类型对炎症刺激的反应 如IL-1 β、TNF-α和内毒素。通过诱导ESE-1表达， 促炎刺激依赖于NF-κ B p50和p65的活化 通过高亲和力NF-κ B结合诱导NSE-1表达的家族成员 在ESE-1启动子中。使用cDNA微阵列，我们已经确定 作为ESE- 1下游靶点的几种炎症反应基因，包括 MMP-1、MMP-13、Fas、DR 5、NOS-2和考克斯-2。促炎诱导 这些基因中的至少两种，NOS-2和考克斯-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是一种新的介导剂， 炎症反应，在调节整个 一组炎症反应基因，并有助于炎症过程， 炎症性疾病。本建议的目的是评估环境、社会和文化事务部的作用， 1在炎症中，采用小鼠慢性肉芽肿组织气囊法 模型作为一种类型的炎症模型和微阵列分析， 确定ESE-1调控的生物学途径。因此，具体目标是： 具体目标#1。ESE-1是ESE-1诱导型的一个重要的直接调节因子吗 目标基因？ 具体目标#2炎症转录程序的哪一部分是由于 ESE-1表达？ 具体目标#3 ESE-1在慢性炎症中发挥作用吗？ 阐明ESE-1在炎症中的功能将提供令人兴奋的 有机会测试ESE- 1是一个新的治疗靶点的假设 用于抗炎药的研发