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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK099204-02
Application #
8822864
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Maruvada, Padma
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
2
Fiscal Year
2015
Total Cost
$391,475
Indirect Cost
$142,128
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Parang, Bobak; Thompson, Joshua J; Williams, Christopher S (2018) Blood Vessel Epicardial Substance (BVES) in junctional signaling and cancer. Tissue Barriers :1-12
Short, Sarah P; Pilat, Jennifer M; Williams, Christopher S (2018) Roles for selenium and selenoprotein P in the development, progression, and prevention of intestinal disease. Free Radic Biol Med 127:26-35
Choksi, Yash A; Reddy, Vishruth K; Singh, Kshipra et al. (2018) BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability. Mucosal Immunol 11:1363-1374
Saito-Diaz, Kenyi; Benchabane, Hassina; Tiwari, Ajit et al. (2018) APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway. Dev Cell 44:566-581.e8
Scoville, Elizabeth A; Allaman, Margaret M; Brown, Caroline T et al. (2018) Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn's Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling. Metabolomics 14:
Thompson, Joshua J; Williams, Christopher S (2018) Protein Phosphatase 2A in the Regulation of Wnt Signaling, Stem Cells, and Cancer. Genes (Basel) 9:
Short, Sarah P; Costacurta, Patricia W; Williams, Christopher S (2017) Using 3D Organoid Cultures to Model Intestinal Physiology and Colorectal Cancer. Curr Colorectal Cancer Rep 13:183-191
McDonough, Elizabeth M; Barrett, Caitlyn W; Parang, Bobak et al. (2017) MTG16 is a tumor suppressor in colitis-associated carcinoma. JCI Insight 2:
Barrett, Caitlyn W; Short, Sarah P; Williams, Christopher S (2017) Selenoproteins and oxidative stress-induced inflammatory tumorigenesis in the gut. Cell Mol Life Sci 74:607-616
Short, Sarah P; Williams, Christopher S (2017) Selenoproteins in Tumorigenesis and Cancer Progression. Adv Cancer Res 136:49-83

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