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Activation of Skin Cells and Transcription Factors by S*

S* 激活皮肤细胞和转录因子

基本信息

批准号：
6446077
负责人：
ROBERT A SWERLICK
金额：
$ 11.4万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2002-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6446077
关键词：
cell adhesion molecules cytokine environmental toxicology gene expression gene induction /repression inflammation intracellular transport messenger RNA nuclear factor kappa beta occupational hazard pathologic process phosphorylation skin skin disorder tissue /cell culture transcription factor

项目摘要

Irritant dermatitis is a major cause of workplace injury. It affects individuals in a variety of work environments and is a source of significant morbidity and lost work time. The pathophysiology of irritant dermatitis is only poorly defined. Exposure of the skin to irritant chemicals results in the rapid appearance of the cardinal features of inflammation associated with cytokine activation and leukocyte infiltration. How irritants activate inflammation is not known. We believe that irritants may activate signaling pathways common to innate immune mechanisms. Centered in these pathways are transcription factors that are linked to pro-inflammatory cytokine genes, cell adhesion molecules, and proteins that trigger capillary leak. One key family of transcription factors linked to the activation of these diverse gene sets is the nuclear factor kappa B (NF-kB) family of transcription factors. Our hypothesis is that irritant exposure results in NF-kB activation in skin cells. This activation results in the triggering of a pro-inflammatory cascade and the clinical appearance of dermatitis. In order to test this hypothesis, we propose the following specific aims: 1) To examine whether irritants can activate NF-kB in cultured skin cells in vitro using epithelial and endothelial cells as targets. We will examine whether irritant treatment of cultured skin cells results in translocation of active NF-kB complexes from the cytoplasm to the nucleus; examine whether irritant treatment of HDMEC, HK, or HDF induces the phosphorylation and ubiquitination of IkBa, necessary steps for proteosome mediated degradation; examine whether translocated NF-kB complexes are capable of binding to relevant response elements of cytokine and cell adhesion molecule gene protomers. 2) To examine whether irritants can activate specific genes in cultured skin cells in vitro using epithelial and endothelial cells as targets. We will examine whether irritants induce or upregulate the expression of adhesion molecules ICAM-1 and E-selectin, and proinflammatory cytokines IL-8 and VEGF-C; examine whether irritants increase steady state mRNA expression of ICAM-1, E-selectin, IL-8, or VEGF-C; examine whether irritant treatment of cultured skin cells results in increase transcription of adhesion molecule or cytokine genes dependent upon NF-kB responsive elements. These studies will provide a framework to define the mechanisms by which irritants cause inflammation in the skin and provide a rational and mechanistic targets for prevention and treatment.

刺激性皮炎是工伤的主要原因。它影响在各种工作环境中的个人，是一个来源，严重的发病率和损失的工作时间。刺激物的病理生理学皮炎的定义很不明确。皮肤暴露于刺激性化学物质导致炎症的主要特征迅速出现与细胞因子活化和白细胞浸润相关。如何刺激激活炎症是未知的。我们认为刺激物会激活先天免疫机制中常见的信号通路。集中在这些途径是与促炎细胞因子相关的转录因子基因、细胞粘附分子和蛋白质引发毛细血管渗漏。一关键家族的转录因子与这些不同的激活基因组是转录核因子κ B（NF-kB）家族因素我们的假设是刺激性暴露导致NF-κ B活化 in skin皮肤cells细胞.这种激活导致促炎性细胞因子的触发。级联反应和皮炎的临床表现。为了测试这种假设，我们提出了以下具体目标：1）检查是否刺激物可以激活体外培养的皮肤细胞中的NF-κ B，和内皮细胞作为靶。我们将研究是否刺激治疗培养的皮肤细胞导致活性NF-kB复合物从细胞质到细胞核;检查HDMEC、HK或 HDF诱导IkBa的磷酸化和泛素化，这是蛋白体介导的降解;检查是否易位的NF-κ B复合物能够与细胞因子和细胞因子的相关反应元件结合，粘附分子基因原体。2)检测刺激物是否能激活使用上皮和内皮细胞体外培养皮肤细胞中的特异性基因细胞作为目标。我们将研究刺激物是否诱导或上调粘附分子ICAM-1和E-选择素的表达以及促炎症反应细胞因子IL-8和VEGF-C;检查刺激物是否增加稳态mRNA ICAM-1、E-选择素、IL-8或VEGF-C的表达;检查是否刺激处理培养的皮肤细胞导致粘附转录增加依赖于NF-κ B应答元件的分子或细胞因子基因。这些研究将提供一个框架来定义刺激物引起皮肤炎症，并提供一个合理的和机械的目标来预防和治疗。