The contributions of Selenoprotein P (Sepp1), a major selenoprotein, to intestinal epithelial homeostasis are unknown. Selenium (Se) is an essential trace element that is incorporated into proteins as selenocysteine. Even under conditions of severe selenium deficiency, the majority of available selenium is used to synthesize Sepp1, highlighting the importance of this protein. Sepp1 has two domains: an amino redox and carboxy Se- rich domain. Sepp1 is expressed in a number of tissues including the intestine and the liver, which is the major source for plasma Sepp1. Little is known about the role of selenium and Sepp1 in inflammatory bowel disease (IBD), a condition of intermittent severe oxidative stress. However, its antioxidant activities suggest that Sepp1 dysfunction could contribute to IBD pathogenesis, particularly during progression to inflammatory neoplasia. In support of this concept, Sepp1 is downregulated in IBD and SNPs in Sepp1 have been associated with advanced adenoma risk. Mechanistically, selenium depletion results in stimulation of the Wnt pathway, which is essential to intestinal stem cell programs and pivotal to mucosal repair in IBD and is one of the first pathways activated in oncogenesis. We have published that selenium deficiency in mice treated with azoxymethane/dextran sodium sulfate, a standard protocol for inflammatory carcinogenesis, had increased mucosal injury and progression to colitis-associated dysplasia (CAD). Likewise, germline Sepp1-deficient mice;as well as mice mutant for redox or Se-rich domains, had increased tumor burden with major effects on proliferation, apoptosis and DNA damage. Abolishing liver-sourced Sepp1 did not phenocopy germline Sepp1 deficiency, providing the first evidence that local Sepp1 production was important for intestinal integrity. Furthermore, Sepp1-/- enteroids have increased stem cell features and hyperplasia. These data suggest that Sepp1 that is locally produced is a major mediator of selenium's effects on epithelial integrity. However, many important questions remain: 1) Does intestinal Sepp1 impact colonic epithelial injury and repair? 2) Does intestinal Sepp1 protect against oxidative stress, mucosal injury and CAD? 3) Which stem cell pathways are modified by Sepp1 in influencing tumorigenesis? 4) Does manipulation of Sepp1 expression influence the growth of established tumors? We hypothesize that intestinal Sepp1 alters the inflammatory microenvironment via clearance of reactive oxygen species thus affecting epithelial stem cell and differentiation programs. We propose to test this hypothesis by using a combination of genetically engineered mice, inducible expression systems, and a newly developed enteroid platform. Collectively, these experiments will allow us to elucidate the role of Sepp1 in mucosal integrity responses and its potential merit as a therapeutic target in IBD.
Inflammatory bowel disease (IBD) affects more than one million Americans and results in a substantial amount of suffering. Selenium is an essential trace element that is incorporated into antioxidant proteins such as Sepp1, a major selenoprotein, which may play a very important role in protecting the intestine from inflammation and malignancy. This research program will define the role of Sepp1 in intestinal injury responses and IBD associated colon cancer.
|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 :|
|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|
|Coburn, Lori A; Horst, Sara N; Allaman, Margaret M et al. (2016) L-Arginine Availability and Metabolism Is Altered in Ulcerative Colitis. Inflamm Bowel Dis 22:1847-58|
|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|
|Pitts, Matthew W; Kremer, Penny M; Hashimoto, Ann C et al. (2015) Competition between the Brain and Testes under Selenium-Compromised Conditions: Insight into Sex Differences in Selenium Metabolism and Risk of Neurodevelopmental Disease. J Neurosci 35:15326-38|
|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|