Deciphering How Aberrant Innate Immune Cells Induce Colitis

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DESCRIPTION (provided by applicant): The precise pathogenesis of inflammatory bowel disease (IBD) is unknown. The aim of this proposal is to obtain further understanding of this human disease by closely examining the pathogenesis of a novel animal model of IBD, the Wiskott-Aldrich Syndrome Protein (WASP) knockout (KO) mice. WASP, the protein defective in patients with Wiskott-Aldrich Syndrome (WAS), is an intracellular signaling molecule expressed exclusively in hematopoietic cells and is involved in actin cytoskeletal rearrangements. Defects in many immune cell subsets have been described in WKO mice and WAS patients, including activation, suppressive function, chemotaxis, antigen presentation, and podosome formation. Most notably, WASP KO mice develop colitis, similar to 10% of WAS patients who suffer from an IBD-like colitis. Preliminary studies have shown that lymphocytes are required and CD4+ T cells are sufficient to transfer disease. More recent data suggest that WKO innate immune cells, potentially dendritic cells (DCs), can convert normal T cells into colitogenic cells. In this proposal, we aim to determine the role of innate immune cells, specifically DCs, in colitis development in WKO mice and to determine what intrinsic defects they may have and how they may aberrantly interact with different T cell subsets to lead to colitis development. Determining the cell types and mechanisms underlying disease onset in this model may aid in our understanding of the pathogenesis of IBD and lead to new targeted therapies. The goal of these next few years is to build my knowledge base, research skills, and experience with independent thinking and scientific writing. The hope is that the result of these next five years of work will yield a basis of discovery leading to a meaningful and profound set of questions that will allow me to become an independent investigator. I plan to pursue an academic career that combines part-time clinical work in the care of IBD patients with the majority of my time spent on basic science research in the field of mucosal immunology. The broader aim is to make a meaningful contribution to the field of mucosal immunology in the hope of someday finding more effective and less toxic treatments for IBD. PUBLIC HEALTH RELEVANCE: Studying the colonic inflammation in mice lacking the Wiskott-Aldrich Syndrome protein, a molecule missing in patients with Wiskott-Aldrich Syndrome, will lead to better understanding of the mechanisms underlying pathogenesis of inflammatory bowel disease (IBD) in humans. Deciphering the specific abnormal cellular population and the factors that mediate their adverse effects will hopefully lead to novel therapies for IBD.