This proposal describes a 5 year training program for the development of an independent translational academic research program. The candidate has completed a structured residency training in Medicine and is completing Gl Fellowship training this year at Vanderbilt University. The proposed program will promote the command of transcriptional corepressor biology, as applied to intestinal inflammatory disease and its sequella. Dr. Scott Hiebert will be the primary mentor for the candidate's scientific development. He is a recognized leader in the field of transcriptional repression and has trained numerous postdoctoral fellows and graduate students. To enhance training, the program will enlist the expertise of Dr. Keith Wilson (Professor of Medicine) and Dr. Brent Polk (Professor of Pediatrics) who have considerable expertise in the field of mucosal immunology and inflammatory bowel disease. In addition, an advisory committee of highly regarded physician scientists will provide scientific and career advice. MTGR1 (Myeloid Translocation Gene, Related-1) is a member of a gene family originally identified as targets of chromosomal translocation in acute myeloid leukemia (AML). Recent work from our laboratory has shown that MTGR1 plays a role in intestinal differentiation, wound healing, and inflammation. We have found that MTG proteins bind TCF4 and repress WNT signal transduction resulting in de-regulation of TCF4 targets. Mtgr1-null animals develop a severe and persistent colitis in response to gut injury and exhibit abnormal enterocyte migration along the crypt-villus access, implicating MTGR1 as a regulator of crypt-villus architectural patterning. Given the role of MTG family members in hematopoietic malignancy, the ability of MTGR1 to modulate WNT signaling, and that loss of MTGR1 results in sensitization to gut injury, we hypothesize that MTGR1 plays a role in inflammatory bowel disease and may contribute to tumorigenesis arising in an inflammatory background.
The specific aims i nclude 1) Defining the role of MTGR1 in proliferation, apoptosis, and migration using cell lines derived from wild-type and Mtgr1-/- mice 2) Dissect the contribution of MTGR1 to carcinogenesis using animal models of inflammatory and non-inflammatory carcinogenesis. Inflammatory Bowel Disease (IBD) is predominantly a disease of the 20th century with highest prevalence in developed countries. Abnormalities in MTG family member function may contribute to IBD susceptibility or pathology and potentially to colitis associated carcinoma and thus may offer therapeutic targets for treatment and or prevention of IBD or IBD associated diseases.
|Barrett, Caitlyn W; Ning, Wei; Chen, Xi et al. (2013) Tumor suppressor function of the plasma glutathione peroxidase gpx3 in colitis-associated carcinoma. Cancer Res 73:1245-55|
|Barrett, Caitlyn W; Singh, Kshipra; Motley, Amy K et al. (2013) Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis. PLoS One 8:e67845|
|Coburn, Lori A; Gong, Xue; Singh, Kshipra et al. (2012) L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis. PLoS One 7:e33546|
|Williams, Christopher S; Zhang, Baolin; Smith, J Joshua et al. (2011) BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma. J Clin Invest 121:4056-69|
|Barrett, Caitlyn W; Fingleton, Barbara; Williams, Amanda et al. (2011) MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model. Cancer Res 71:1302-12|
|Russ, Patricia K; Pino, Christopher J; Williams, Christopher S et al. (2011) Bves modulates tight junction associated signaling. PLoS One 6:e14563|
|Hong, Shih-Kuang S; Chaturvedi, Rupesh; Piazuelo, M Blanca et al. (2010) Increased expression and cellular localization of spermine oxidase in ulcerative colitis and relationship to disease activity. Inflamm Bowel Dis 16:1557-66|
|Whittem, Caitlyn G; Williams, Amanda D; Williams, Christopher S (2010) Murine Colitis modeling using Dextran Sulfate Sodium (DSS). J Vis Exp :|