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: 8484392
• 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/8484392
• 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.

这项应用建议研究Toll样受体4阳性(TLR4)T细胞在调节 小鼠模型中的炎症性肠病。免疫调节过程中TLR4+T淋巴细胞的产生 肠道蠕虫感染。它们识别细菌脂多糖(LPS)并产生免疫 当被脂多糖刺激时，可调节转化生长因子-β，但不能调节促炎细胞因子。我们假设 内毒素刺激的粘膜T细胞分泌转化生长因子-β对肠道免疫调节具有重要意义。我们建议 为了在未发炎的野生型或结肠炎动物和小鼠中验证我们的假设 参与TLR4信号通路的蛋白质的遗传缺陷，如MyD88-/-或TRIF-/-小鼠 菌株。在某些实验中，我们计划使用药理药物或补充短波抑制。 RNA(SiRNA)结构抑制TLR4信号通路的某些元件。具体目标1：我们将 测定内毒素刺激后TLR4+肠道T细胞的表型和功能变化。特定的 目的#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细胞在肠道的诱导或维持中的作用 结肠炎小鼠模型的免疫平衡。这一建议可能会导致对新细胞的鉴定 在IBD控制中起重要作用的蛋白质。通过药理学药物靶向这些分子可能会导致 有效和安全的炎症性肠病医疗管理。 这项建议的长期目标是将首席调查员提升为独立的医生 胃肠病学和粘膜免疫学的科学家，在细胞和分子方面有丰富的背景 生物学。申请人于2007年在爱荷华大学完成胃肠病学研究，现为 在他被任命为终身教职助理教授的第一年。这项研究将在 由大卫·埃利奥特博士、保罗·罗斯曼博士和加里·亨宁哈克博士指导的爱荷华大学。在……里面 此外，一个由教职员工组成的咨询委员会将提供职业发展建议。获奖名单 将使首席研究人员掌握细胞和分子生物学的研究技能。