TLR5-mediated signaling in gut epithelia

描述（由申请人提供）：胃肠道上皮细胞是抵御共生和潜在病原微生物的第一线。根据这一作用，当微生物破坏肠上皮时，这些细胞激活基因表达，促进先天免疫炎症反应和随后的适应性免疫调节。我的赞助人已经证明肠上皮细胞检测微生物的主要手段是toll样受体5 （TLR5）介导的细菌鞭毛蛋白检测。由于TLR5识别来自共生微生物和致病微生物的鞭毛蛋白，因此TLR5的生物学特性可能与理解先天免疫和以对共生微生物的粘膜免疫失调为特征的疾病（如炎症性肠病）密切相关。我们对TLR5信号知之甚少，除了我的赞助人证明它，而不是任何其他tlr，在鞭毛蛋白的反应中赋予nf - kappab介导的基因表达。虽然许多促炎激动剂激活NF-kappaB，但我的赞助人及其合作者和其他人的新研究表明，不同促炎激动剂诱导的基因表达总体模式存在明显差异。本研究研究了TLR5激活一种特定的信号转导事件模式，介导鞭毛蛋白诱导的上皮基因表达变化的假设。具体来说，我建议研究MAP激酶、Ca++动员和STAT激活在调节tlr5介导的肠上皮基因表达中的作用。

DESCRIPTION (provided by applicant): Epithelial cells lining the gastrointestinal tract are the front line of defense against commensally and potential pathogenic microbes. In accordance with this role, upon microbial breach of the intestinal epithelium, these cells activate expression of genes that promote an innate immune inflammatory response and subsequent regulation of adaptive immune immunity. My sponsor has demonstrated that a primary means by which intestinal epithelial cells detect microbes is toll-like receptor 5 (TLR5)-mediated detection of bacterial flagellin. Since TLR5 recognizes flagellins from commensally and pathogenic microbes, the biology of TLR5 is likely germane to understanding both innate immunity and diseases characterized by dysregulated mucosal immunity toward commensally microbes such inflammatory bowel disease. Little is known about TLR5 signaling beyond my sponsor's demonstration that it, but not any other TLRs, confer NF-kappaB-mediated gene expression in response to flagellin. While many pro-inflammatory agonists activate NF-kappaB, emerging studies by my sponsor, his collaborators, and others indicate that there are distinct differences in the overall patterns of gene expression induced by different proinflammatory agonists. This proposal investigates the hypothesis that TLR5 activates a specific pattern of signal transduction events that mediate flagellin-induced changes in epithelial gene expression. Specifically, I propose to examine the role of MAP kinases, Ca++-mobilization, and STAT activation in regulated TLR5-mediated gene expression in gut epithelia.