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.
Exposure to helminths may prevent the development of inflammatory bowel disease. Unlike other immune suppressive medications used, helminths may also control intestinal inflammation without causing severe adverse effects. This application proposes to investigate the mechanism how helminths control colitis and may lead to the identification of novel, safer Inflammatory bowel disease treatment.
|Li, Yue; Chen, Hung-Lin; Bannick, Nadine et al. (2015) Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice. J Immunol 194:1011-20|
|Ince, M Nedim; Elliott, David E; Setiawan, Tommy et al. (2009) Role of T cell TGF-beta signaling in intestinal cytokine responses and helminthic immune modulation. Eur J Immunol 39:1870-8|