Role of TLR4 in Acute and Chronic Murine Colitis

描述（由申请方提供）：一方面，肠上皮和肠道相关粘膜免疫系统必须对病原菌产生炎症反应，同时积极限制肠道生物体的炎症。炎症性肠病（IBD）在遗传易感宿主中在触发事件后发展。第一个被确定为克罗恩病疾病易感基因的基因是CARD 15/NOD 2，一种细胞内病原体识别受体（PRR）。克罗恩病相关的多态性在CARD 15/NOD 2基因导致蛋白质，这是在其激活NF-κ B的能力受损，以响应肽聚糖。这些数据表明，先天性免疫反应缺陷的肠道或病原菌可能最终导致慢性肠道炎症。Toll样受体（TLR）也是PRR。PAMP与其各自TLR的结合导致NF-κ B活化和细菌清除。TLR 4是存在于革兰氏阴性菌上的脂多糖（LPS）的受体。本申请源于我们令人惊讶的初步观察，即具有TLR 4无效突变（TLR 4-/-）的小鼠在施用葡聚糖硫酸钠后具有增加的结肠炎临床症状、缺乏嗜酸性浸润和增加的细菌易位。在MyD 88-/-小鼠中观察到类似的结果，表明这是导致这种表型的TLR 4下游的主要途径。基于我们的初步数据，我们希望测试的假设，通过TLR 4的信号传导是必需的产生急性炎症反应肠损伤和限制慢性肠道炎症的发展。我们将利用来自R21的支持来产生强大的动物模型，以建立在肠道炎症的起始和持续中对TLR 4的需求。

DESCRIPTION (provided by applicant): The intestinal epithelium and gut-associated mucosal immune system must on the one (1) hand generate an inflammatory response to pathogenic bacteria while actively limiting inflammation to commensal organisms. Inflammatory bowel disease (IBD) develops in the genetically-susceptible host following a triggering event. The first gene to be identified as a disease-susceptibility gene in Crohn's disease is CARD15/NOD2, an intracellular pathogen-recognition receptor (PRR). Crohn's disease-associated polymorphisms in the CARD15/NOD2 gene result in a protein that is impaired in its ability to activate NF-kB in response to peptidoglycan. This data suggests that a defect in the innate immune response to commensal or pathogenic bacteria may culminate in chronic intestinal inflammation. Toll-like receptors (TLRs) are also PRRs. Binding of PAMPs to their respective TLRs results in NF-kB activation and clearance of bacteria. TLR4 is the receptor for lipopolysaccharide (LPS) present on Gram-negative bacteria. This application emanates from our surprising preliminary observation that mice with a null mutation in TLR4 (TLR4-/-) have increased clinical symptoms of colitis following administration of dextran sodium sulfate, a paucity of neutrophilic infiltration, and increased bacterial translocation. Similar results were observed in MyD88-/- mice suggesting this is the dominant pathway downstream of TLR4 accounting for this phenotype. Based on our preliminary data, we wish to test the hypothesis that signaling through TLR4 is required for the generation of an acute inflammatory response to intestinal injury and limiting the development of chronic intestinal inflammation. We will use the support from this R21 to generate robust animal models that establish the requirement for TLR4 in the initiation and perpetuation of intestinal inflammation.