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: 8312727
• 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/8312727
• 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

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.

本申请旨在研究 Toll 样受体 4 阳性 (TLR4) T 细胞在调节中的作用 小鼠模型中的炎症性肠病。 TLR4+ T淋巴细胞在免疫调节过程中出现 肠道内的蠕虫感染。它们识别细菌脂多糖（LPS）并产生免疫 当用 LPS 刺激时，调节 TGF-β，但不调节促炎细胞因子。我们假设 LPS刺激粘膜T细胞分泌TGF-β对于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和小鼠的 H. polygyrus 感染模型中检验我们的假设 参与 TLR4 信号通路的蛋白质存在遗传缺陷，例如 MyD88-/- 或 TRIF-/- 小鼠 菌株。在某些实验中，我们计划使用药物或补充性短抑制剂 RNA (sIRNA) 会抑制 TLR4 信号通路的某些元件。具体目标#1：我们将 确定 LPS 刺激后 TLR4+ 肠道 T 细胞的表型和功能变化。具体的 目标#2：我们将定义肠道 TLR4+ T 细胞中导致 TGF-β 产生的信号元件。 具体目标#3：我们将确定 TLR4+ T 细胞在诱导或维持肠道功能中的作用。 结肠炎小鼠模型中的免疫平衡。该提议可能会导致新型细胞的鉴定 控制 IBD 的重要蛋白质。通过药物靶向这些分子可能会导致 炎症性肠病的有效且更安全的医疗管理。 该提案的长期目标是将主要研究者晋升为独立医生 胃肠病学和粘膜免疫学科学家，具有丰富的细胞和分子背景 生物学。申请人于 2007 年在爱荷华大学完成了胃肠病学奖学金，并且是 在他被任命为终身教授助理教授的第一年。该研究将在 爱荷华大学在博士的指导下。大卫·埃利奥特、保罗·罗斯曼和加里·亨宁哈克。在 此外，一个由教员组成的咨询委员会将提供职业发展建议。所获奖项 将使主要研究者掌握细胞和分子生物学的研究技能。