The Role of Toll-like Receptor 4 Positive T Cells in Intestinal Immune Regulation

描述（由申请人提供）： 本申请提出在小鼠模型中研究Toll样受体4阳性（TLR 4）T细胞在调节炎性肠病中的作用。TLR 4 + T淋巴细胞在肠道免疫调节蠕虫感染期间出现。它们识别细菌脂多糖（LPS），并在LPS刺激时产生免疫调节性TGF-β，但不产生促炎细胞因子。我们假设LPS刺激的粘膜T细胞TGF-β分泌对肠道免疫调节很重要。我们建议在H中检验我们的假设。在未发炎的野生型或结肠炎动物中以及在参与TLR 4信号传导途径的蛋白质遗传缺陷的小鼠（如MyD 88-/-或TRIF-/-小鼠品系）中的多脑回感染模型。在某些实验中，我们计划使用药物或互补的短抑制RNA（siRNA）结构来抑制TLR 4信号通路的某些元件。具体目标#1：我们将确定LPS刺激后TLR 4+肠T细胞的表型和功能变化。具体目标#2：我们将确定导致TGF-β产生的肠道TLR 4 + T细胞中的信号传导元件。具体目标#3：我们将确定TLR 4 + T细胞在结肠炎小鼠模型中诱导或维持肠道免疫平衡的作用。这一建议可能会导致新的细胞蛋白质的重要控制IBD的鉴定。通过药理学药物靶向这些分子可能导致炎症性肠病的有效和更安全的医学管理。本提案的长期目标是将主要研究者提升为胃肠病学和粘膜免疫学领域的独立医生科学家，并具有细胞和分子生物学的重要背景。申请人于2007年在爱荷华州大学完成了胃肠病学奖学金，并在他被任命为终身助理教授的第一年。这项研究将在爱荷华州大学进行，由大卫埃利奥特博士、保罗罗斯曼博士和加里亨宁哈克博士指导。此外，一个由教师组成的咨询委员会将提供职业发展建议。该奖项将使首席研究员掌握细胞和分子生物学的研究技能。

DESCRIPTION (provided by applicant): This application proposes to investigate the role of toll-like receptor 4 positive (TLR4) T cells in regulating inflammatory bowel disease in mouse models. TLR4+ T lymphocytes emerge during immune modulatory helminth infection in the intestine. They recognize bacterial lipopolysaccharide (LPS) and produce immune regulatory TGF-beta but not proinflammatory cytokines, when stimulated with LPS. We hypothesize that LPS-stimulated mucosal T cell TGF-beta secretion is important for intestinal immune regulation. We propose to test our hypothesis in H. polygyrus infection model in uninflamed wild-type or colitic animals and in mice genetically deficient for proteins that participate in TLR4 signaling pathway, like MyD88-/- or TRIF-/- mouse strains. In certain experiments we plan to employ pharmacologic agents or complementary short inhibitory RNA (siRNA) contructs to inhibit certain elements of TLR4 signaling pathway. Specific Aim #1: We will determine phenotypic and functional changes in TLR4+ intestinal T cells following LPS stimulation. Specific Aim #2: We will define the signaling elements in intestinal TLR4+ T cells that lead to TGF-beta production. Specific Aim #3: We will identify the role of TLR4+ T cells in the induction or maintenance of intestinal immune balance in mouse models of colitis. This proposal may lead to the identification of novel cellular proteins important in the control of IBD. Targeting these molecules by pharmacologic agents may lead to potent and safer medical management of inflammatory bowel disease. The long-term objective of this proposal is to advance the principal investigator to an independent physician scientist in gastroenterology and mucosal immunology with significant background in cellular and molecular biology. The applicant has completed fellowship in gastroenterology at the University of Iowa in 2007 and is in his first year of appointment as an assistant professor on tenure track. The research will take place at the University of Iowa under the mentorship of Drs. David Elliott, Paul Rothman and Gary Hunninghake. In addition, an advisory committee of faculty members will provide career development advice. The award would allow the principal investigator to master research skills in cellular and molecular biology.