The precise pathogenesis of inflammatory bowel disease (IBD) is unknown.
The aim of this proposal is to obtain further understanding of how actin cytoskeletal regulation is involved in controlling mucosal immune homeostasis. We have previously shown that deficiency of Wiskott-Aldrich Syndrome Protein (WASP), an intracellular signaling molecule involved in actin cytoskeletal rearrangements, can lead to spontaneous colitis in humans and mice. This colitis is dependent on the presence of lymphocytes and is transferrable by transferring WASP-deficient T cells. Rac1 and Rac2 are isoforms of small GTPases that also control actin cytoskeletal rearrangements. Like WASP-deficient mice, our preliminary data suggest animals lacking Rac2 also demonstrated decreased regulatory T cells, and recent published data suggest increased propensity for Citrobacter-induced colitis in these mice, although we observe protection in other models of colitis. In addition, recent genetic analyses have demonstrated an association between single nucleotide polymorphisms (SNPs) in Rac1 and Rac2 and IBD risk. Therefore, the actin regulatory network, particularly Rac1 and Rac2, appears to play a role in mucosal immunity. In this proposal, we aim to further character the role of Rac1 and/or Rac2 in regulatory and effector T-cell generation, survival, and migration and determine whether defects are intrinsic to the T cells or secondary to innate immune priming and education. Determining the mechanisms underlying how actin regulation controls mucosal T cell biology may aid in our understanding of the pathogenesis of IBD and lead to new targeted therapies. The goal of this proposal is to build upon current preliminary data in preparation for an R01 application in the coming 1-2 years, which will focus more on the manner in which actin rearrangements may function to regulate T-cell phenotype at a molecular level and innate immune cell-T cell interactions that maintain mucosal homeostasis. 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.
Studying the cellular and molecular signals by which immune cells are regulated will lead to better understanding of the mechanisms responsible for the development of inflammatory bowel disease (IBD) in humans. Furthermore, finding the specific abnormal cellular population(s), how they interact with each other, and the factors that mediate their adverse effects will hopefully lead to novel therapies for IBD.