PAKs in IBD and associated intestinal cancer

Inflammatory bowel diseases (IBD) are characterized as persistent and recurring intestinal inflammation which increases the risk of developing colitis-associated-cancer (CAC). Two main forms of IBD are ulcerative colitis (UC) and Crohns disease. This project intends to underscore the role of p-21-activated kinase1 (PAK1) in UC and CAC. We identified PAK1 as a molecular target of mesalamine (primary treatment for UC). PAK1 acts as an enzyme that phosphorylates several proteins and modifies their cellular functions like cell survival, motility, wound healing and hence orchestrates multiple molecular pathways. Our research findings indicate that PAK1 expression is increased in IBD and CAC in both humans and in animal models. Other studies have also implicated PAK signaling in driving colitis and cancer progression. Understanding how this molecule contributes to disease will provide novel information, which can be utilized for improvising current therapy in IBD and for developing new chemo-preventive approaches in CAC. We propose to generate a novel mouse model with tissue specific deletion of PAK1 to help us elucidate its specific role in intestinal epithelium, where it is overexpressed in these diseases. We would examine the effect of PAK1 deletion on the mechanisms of colitis and intestinal carcinogenesis in these mice: (1) by experimentally inducing colitis and CAC (AOM/DSS model); (2) by examining susceptibility to spontaneous development of colitis and cancer using a genetic mouse model of IBD (IL-10 KO; IL-10 knockout mice in which IL-10 gene is deleted) that spontaneously develops colitis. For this, mice with tissue-specific PAK1 deletion are crossed with IL-10 KO mice. We will further utilize intestinal organoids (three dimensional self-organizing mini-structures mimicking intestinal tissue) established from these mice, to investigate cellular pathways implicated in IBD and CAC. PAK1 belong to a family of proteins having overlapping as well as distinct functions. It is possible that other PAKs which are also expressed in intestinal tissue (PAK2, PAK4) contribute to the disease development. Therefore, we propose to examine these PAKs in human tissue samples as well as in these mouse models. The molecular players of PAK signaling could not only be targeted for therapeutic interventions, but also be used as a biomarker of disease surveillance. The outcome of this project will prompt new investigations to understand PAK signaling in the maintenance of gut health.

In this project we studied the role of a specific protein called PAK1 on the role of intestinal inflammation and carcinogenesis. PAK1 is an important protein of intestinal homeostasis, but has many unknowns functions, one of which is regulation of oxidative stress and associated inflammatory response or DNA mutations.