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.
|Parang, B; Bradley, A M; Mittal, M K et al. (2016) Myeloid translocation genes differentially regulate colorectal cancer programs. Oncogene 35:6341-6349|
|Barrett, Caitlyn W; Short, Sarah P; Williams, Christopher S (2016) Selenoproteins and oxidative stress-induced inflammatory tumorigenesis in the gut. Cell Mol Life Sci :|
|Parang, Bobak; Barrett, Caitlyn W; Williams, Christopher S (2016) AOM/DSS Model of Colitis-Associated Cancer. Methods Mol Biol 1422:297-307|
|Reddy, Vishruth K; Short, Sarah P; Barrett, Caitlyn W et al. (2016) BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation. Stem Cells 34:1626-36|
|Parang, Bobak; Rosenblatt, Daniel; Williams, Amanda D et al. (2015) The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation. FASEB J 29:786-95|
|Poindexter, Shenika V; Reddy, Vishruth K; Mittal, Mukul K et al. (2015) Transcriptional corepressor MTG16 regulates small intestinal crypt proliferation and crypt regeneration after radiation-induced injury. Am J Physiol Gastrointest Liver Physiol 308:G562-71|
|Williams, Christopher S; Bernard, Jessica K; Demory Beckler, Michelle et al. (2015) ERBB4 is over-expressed in human colon cancer and enhances cellular transformation. Carcinogenesis 36:710-8|
|Barrett, Caitlyn W; Reddy, Vishruth K; Short, Sarah P et al. (2015) Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage. J Clin Invest 125:2646-60|
|Williams, Christopher S; Bradley, Amber M; Chaturvedi, Rupesh et al. (2013) MTG16 contributes to colonic epithelial integrity in experimental colitis. Gut 62:1446-55|
|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|
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