DESCRIPTION (provided by applicant): As an Assistant Professor of Medicine in the Division of Gastroenterology at Washington University School of Medicine, I am focused on exploring mechanisms whereby deletion of a myofibroblast protein results in protection from colitis and colitis associated cancer (CAC). Immediate and long-term career goals: This award will allow time to obtain didactic training and technical expertise, and publish additional first-authored manuscripts detailing the role of the stroma and colonic myofibroblast in the development of CAC, with the goal of applying for independent funding in the form of an R01 in year 4 of this award. In the long-term I hope to transition to an independent investigative career as a physician-scientist in gastroenterology, investigating the stroma in the pathogenesis of inflammation associated cancer. Career development: Inpatient clinical duties are limited to < 25% of my time. In addition to completing the aims of my research proposal, my career development plan consists of individual and group meetings with mentors Drs. Rubin and Newberry, meetings with my Advisory Committee, conferences in the GI Division and the School of Medicine, participation in national conferences including DDW, FASEB, and AAI, and instruction in bone marrow transfer, flow cytometry, and laser capture microdissection. I plan on completing Aim 1 studies and detailing my findings in a manuscript by the end of year 1; completing a substantial portion of Aim 2 along with a manuscript by years 2-3; and completing Aim 2 studies and a manuscript in years 4-5. Environment: The research and educational resources of Washington University School of Medicine and the Gastroenterology Division have contributed to the generation of successful physician-scientists. My mentors Drs. Rubin and Newberry are well-established experts in stromal/epithelial and immune cellular biology and have committed to providing training for the proposed research project. Research: Disrupted epithelial-stromal interactions are implicated in the pathogenesis of colitis and CAC. Epimorphin (epim) is a stromal and myofibroblast protein that regulates intestinal epithelial morphogenesis. Epim-/- mice are partially protected from acute colitis in association with an increase in crypt cell proliferation. We have shown in a murine model of CAC that Epim-/- mice have markedly reduced dysplastic tumor burden. We have also demonstrated that epimorphin deletion increases secretion of Chordin from colonic myofibroblasts and decreases secretion of Interleukin-6 (IL-6) from myofibroblasts and macrophages. We propose that these regulatory events are important because Chordin inhibits bone morphogenetic protein (Bmp), a protein known to inhibit crypt cell proliferation. In addition, IL-6 is a pro-inflammatory cytokine that has been implicated in CAC. These observations underlie our two major hypotheses: Hypothesis 1: Epimorphin deletion alters colonic myofibroblast secretion of key signaling molecules that regulate crypt cell proliferation (Bmps and Bmp inhibitors) and modulate inflammation (cytokines). Hypothesis 2: Epimorphin deletion alters the secretory function of bone marrow derived myofibroblasts and stromal cells which play a significant role in conferring protection from colitis and CAC. These related hypotheses will be pursued in the following specific aims: 1. Determine the mechanisms by which epimorphin deletion results in an increase in epithelial crypt cell proliferation and reduced inflammation. These studies will address hypothesis 1. We will use Epim-/- and WT myofibroblasts and myofibroblast-epithelial co-cultures to examine the effect of epimorphin deletion on colonic myofibroblast secretion of signaling molecules involved in the regulation of crypt cell proliferation (Bmps) and inflammation (cytokines). We will extend these observations to the dextran sodium sulfate (DSS) colitis and azoxymethane (AOM)/DSS CAC models. We predict epi |