This proposal is based on the hypothesis that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) will provide a novel, safe, and effective therapy for inflammatory bowel diseases (IBD). Inflammatory bowel diseases are marked by recurrent bouts of abdominal pain and bloody diarrhea along with other manifestations, and affect an estimated 1.1 million people in the United States. Current treatment options such as aminosalicylates, corticosteroids, and anti-TNF-a agents are associated with adverse effects and are imperfect in inducing a clinical response, with surgery still required for 20% of ulcerative colitis and 66% of Crohn's disease patients. Thus, there is a need for more effective therapies. Prostaglandin E2 (PGE2) maintains many functions of the gastrointestinal tract and is important in cellular proliferation after mucosal injury. Blocking th effects of PGE2 is associated with exacerbated colitis in IBD animal models; whereas, increasing PGE2 signaling ameliorates disease. 15-PGDH is the enzyme responsible for the rate-limiting step of PGE2 metabolism. This proposal explores the hypothesis that inhibition of 15-PGDH is a preferred and effective method to increase tissue PGE2 levels in the intestine and will provide a safe and effective therapy for IBD. To explore this treatment idea, a novel high-affinity inhibitor of 15-PGDH, SW033291, with in vivo stability has been identified. In this proposal, this inhibitor will be used to investigate the effects of modulating 15-PGDH directly in mice models of IBD. In this study, we will first directly determine the effects of SW033291 on disease activity in a mouse model of ulcerative colitis. Our hypothesis is that inhibition of 15-PGDH will markedly ameliorate disease severity through a mucosal protective effect mediated by effects of increased PGE2 on maintenance of stem and proliferating cells in the colonic crypts. To interrogate this proposed mechanism, the effects of inhibiting 15-PGDH on distinct colonic crypt cell populations will be assessed using both stem cell reporter mice (to examine LGR5 and LRIG1 marked colonic stem cells) and BrdU incorporation (to examine both stem cells and transit amplifying cells in the crypt). Moreover, as IBD-associated cancer development is independent of cyclooxygenases, the enzymes responsible for synthesizing prostaglandins, we hypothesize that inhibiting 15-PGDH will decrease colitis-associated colon cancer risk, i.e. we hypothesize that the effects of SW033291 on reducing colitis disease activity and lowering cancer risk will dominate the pro- proliferative effects of PGE2 that are associated with cancer risk in models of non-colitis associated cancer. Taken together, these experiments will provide an in-depth characterization of 15-PGDH as a new molecular target for treating IBD and will establish a solid translational foundation for using 15-PGDH inhibitor therapy in treating IBD patients. This project will further provide me a solid foundation and training for pursuing my personal goals of a career in academic medicine and medical research.
Over a million people in the United States suffer from inflammatory bowel diseases (IBD), which cause recurrent episodes of abdominal pain and bloody diarrhea. Current treatment options often induce imperfect responses and generally have many undesirable side effects, fueling the ongoing search for more effective therapies. This research project seeks to explore the feasibility of targeting an important enzyme involved in maintaining the functions of the gastrointestinal tract, 15-hydroxyprostaglandin dehydrogenase enzyme, by using a novel molecule and established animal models of IBD; successful completion of this study may provide a new, promising approach for treating patients with IBD.
