Mechanisms and Prevention of TGF-beta-induced Intestinal Fibrosis

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This proposal describes a 3-vear training program for the development of an academic research career in translational research in inflammatory bowel disease. The principal investigator has completed molecular biology training (Ph.D.), and clinical research training (M.Sc.), and will now link basic science and clinical research skills with supplementary training in orphan nuclear receptor biology and transgenic rodent models of intestinal fibrosis. This will provide a critical link to enable the candidate to translate basic science findings to future clinical research in humans. The training program will develop the candidate's skills in nuclear receptor biology, myofibroblast biology, and intestinal fibrosis, through structured learning and an outstanding mentoring team. Dr. Ellen Zimmermann, an expert in intestinal fibrosis, will be joined on the mentoring team by Dr. Sem Phan, an expert in myofibroblast biology, Dr. Victor Thannickal, a translational researcher in pulmonary fibrosis, and Dr. Bertram Pitt, a clinical researcher of the role of spironolactone in cardiac fibrosis and heart failure. The Gastroenterology Division at the University of Michigan provides an ideal setting for training translational physician-scientists by incorporating expertise from many resources into customized training programs for academic career development. This environment is highly advantageous for launching the translational research career of Dr. Higgins. The proposed research will focus on intestinal fibrosis, a feared complication of Crohn's disease with no effective medical treatments. The long-term research goal is to elucidate the mechanisms of TGF|31-driven intestinal fibrosis and to use this information to target anti-fibrotic therapies that can prevent or reverse intestinal fibrosis. Our preliminary data drives our central hypothesis, that spironolactone has a novel property, the ability to inhibit TGF(31 signaling via SMAD2 and SMAD3 through its activation of the orphan nuclear receptor, PXR (pregnane X receptor). The specific aims include: (1) To determine whether spironolactone utilizes activation of the pregnane X receptor (PXR)to prevent phosphorylation, nuclear translocation, or the transcriptional activity of Smad2 and SmadS in TGF-(31 stimulated fibrogenic colonic myofibroblasts; and (2) To determine whether spironolactone can inhibit intestinal fibrosis in rat and mouse models of chronic inflammatory bowel disease. These studies will provide insight into the mechanisms of TGF31 -driven intestinal fibrosis, will help the candidate develop essential skills to become an independent investigator, and may provide the basis of future translational applications of anti-fibrotic therapy. This research is highly relevant to public health because Crohn's disease affects over 600,000 Americans; we have no therapy to prevent intestinal fibrosis; and currently -75% of these patients will eventually require surgery for fibrotic intestinal strictures.