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

Toll样受体4阳性T细胞在肠道免疫调节中的作用

• 批准号: 8082745
• 负责人: Mirac Nedim Ince
• 金额: $ 14.75万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082745
• 关键词: Adverse effects; Advisory Committees; Animals; Antigens; Appointment; Award; Bacteria; CD14 gene; Cell Culture Techniques; Cells; Colitis; Development; Disease model; Distal; Elements; Equilibrium; Exposure to; Faculty; Fellowship; Gastroenterology; Generations; Helminths; Immune; Immune response; Immunology; In Vitro; Indium; Individual; Infection; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Instruction; Intestines; Iowa; Lamina Propria; Lead; Lipopolysaccharides; Maintenance; Mediating; Medical; Mentorship; Modeling; Molecular and Cellular Biology; Mononuclear; Mouse Strains; Mucous Membrane; Mus; Nematoda; Nematospiroides dubius; Parasites; Pathway interactions; Pharmaceutical Preparations; Physicians; Principal Investigator; Production; Proteins; RNA; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Role; Scientist; Signal Pathway; Signal Transduction; T cell response; T-Lymphocyte; Testing; Toll-like receptors; Transforming Growth Factor beta; Universities; career development; commensal microbes; cytokine; immunoregulation; member; mouse model; mouse toll-like receptor 4; novel; pathogen; prevent; professor; receptor; research study; response; skills; toll-like receptor 4

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.

描述(由申请人提供)： 这项应用旨在研究Toll样受体4阳性(TLR4)T细胞在调节小鼠炎症性肠病模型中的作用。肠道免疫调节性蠕虫感染时会产生TLR4+T淋巴细胞。当细菌脂多糖(LPS)刺激时，它们识别细菌脂多糖，并产生免疫调节性转化生长因子-β，但不产生促炎细胞因子。我们推测，内毒素刺激的粘膜T细胞转化生长因子-β的分泌对肠道免疫调节很重要。我们建议在未发炎的野生型或结肠炎动物以及参与TLR4信号通路蛋白质遗传缺陷的小鼠身上，如MyD88-/-或TRIF-/-小鼠品系中，在多回H.Polygyus感染模型中验证我们的假设。在某些实验中，我们计划使用药物或互补的短抑制性RNA(SiRNA)结构来抑制TLR4信号通路的某些元件。具体目标1：我们将确定TLR4+肠道T细胞在脂多糖刺激后的表型和功能变化。具体目标2：我们将确定肠道TLR4+T细胞中导致转化生长因子-β产生的信号元件。具体目标#3：我们将确定TLR4+T细胞在诱导或维持小鼠结肠炎模型肠道免疫平衡中的作用。这一建议可能导致识别在控制IBD方面重要的新的细胞蛋白。通过药物靶向这些分子可能会导致对炎症性肠病的有效和安全的医疗治疗。这项建议的长期目标是将首席研究员提升为胃肠病学和粘膜免疫学方面的独立内科科学家，具有重要的细胞和分子生物学背景。申请者于2007年在爱荷华大学完成了胃肠病学研究，目前是他被任命为终身教职助理教授的第一年。这项研究将在爱荷华大学进行，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。该奖项将允许首席研究员掌握细胞和分子生物学的研究技能。