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 epimorphin deletion will alter myofibroblast secretion of Bmps and cytokines to increase epithelial cell proliferation and reduce inflammation. 2. Define the identity and origin of the cells that are responsible for protection from DSS colitis and AOM/DSS CAC in Epim-/- mice. These studies will address hypothesis 2. Myofibroblasts are resident in the intestinal stroma but in the setting of injury or inflammation, """"""""new"""""""" myofibroblasts and other bone marrow (BM) derived stromal cells migrate into the intestine. To determine whether the observed phenotype in Epim-/- mice is a consequence of BM derived cells, we will perform GFP labeled Epim-/- and WT BM rescue of lethally irradiated Epim-/- and WT recipients and treat BM chimeras with DSS and AOM/DSS. We will determine the cellular identify of the transplanted BM cells in the recipient and define their cytokine secretory profile. We predict that Epim-/- BM donor derived cells will be required to achieve maximal protection from DSS colitis and AOM/DSS dysplasia. These studies may provide the basis for novel therapeutic approaches to inflammatory bowel disease and CAC.

Public Health Relevance

Disrupted epithelial-stromal interactions are increasingly implicated in the pathogenesis of colitis associated cancer, a known long-term complication of the inflammatory bowel diseases (IBD) ulcerative colitis and Crohn's disease. We aim to investigate the role of the stromal myofibroblast in the pathogenesis of this sub- type of colorectal cancer (CRC). Research on the cellular and molecular pathogenesis of IBD related colon cancer increases the potential of developing targeted therapies for this difficult to treat malignancy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
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Subcommittee B - Comprehensiveness (NCI)
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Perkins, Susan N
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University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
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Niu, Chao; Chauhan, Uday; Gargus, Matthew et al. (2016) Generation and Characterization of an Immortalized Human Esophageal Myofibroblast Line. PLoS One 11:e0153185
Gargus, Matthew; Niu, Chao; Vallone, John G et al. (2015) Human esophageal myofibroblasts secrete proinflammatory cytokines in response to acid and Toll-like receptor 4 ligands. Am J Physiol Gastrointest Liver Physiol 308:G904-23
Gargus, Matthew; Niu, Chao; Shaker, Anisa (2015) Isolation of myofibroblasts from mouse and human esophagus. J Vis Exp :52215
Shaker, Anisa; Gargus, Matthew; Fink, Julie et al. (2014) Epimorphin(-/-) mice are protected, in part, from acute colitis via decreased interleukin 6 signaling. Transl Res 164:70-83
Shaker, Anisa; Binkley, Jana; Darwech, Isra et al. (2013) Stromal cells participate in the murine esophageal mucosal injury response. Am J Physiol Gastrointest Liver Physiol 304:G662-72
Shaker, Anisa; Rubin, Deborah C (2012) Stem cells: One step closer to gut repair. Nature 485:181-2
Rubin, Deborah C; Shaker, Anisa; Levin, Marc S (2012) Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Front Immunol 3:107
Thaker, Ameet I; Shaker, Anisa; Rao, M Suprada et al. (2012) Modeling colitis-associated cancer with azoxymethane (AOM) and dextran sulfate sodium (DSS). J Vis Exp :