Induction of mucosal healing in inflammatory bowel disease (IBD) is associated with reduced hospitalizations and surgeries. Healing of the mucosal barrier requires control of the destructive inflammatory response as well as restitution of the epithelial barrier through enhanced proliferation and generation of new crypt structures. Although it is clear that induction of Wnt/B-catenin activation is a key factor in intestinal stem ell (ISC) and progenitor cell (PC) activation, there are few researchers that examine the regulation of B-catenin activation in colitis where mucosal healing and inflammation-induced dysplasia are major clinical concerns. Studies performed during the prior award period demonstrated that Akt phosphorylation of B-catenin increases in ISCs during colitis and colitis-induced cancer. The present proposal makes use of a novel genetic model for reducing PI3K signaling in colonic intestinal epithelial cells (IEC) during colitis. Data already produced in VilCre/pik3r1fl/fl mice given DSS colitis suggest that PI3K-mediated B-catenin activation plays a major role in wound healing. Acute and chronic forms of DSS colitis will be generated in VilCre/pik3r1fl/fl mice for in vivo studies in AIM 1 to examine the role of IEC class 1A PI3K in mucosal healing, B-catenin activation and ISC/PC gene expression (using novel enteroid cultures). Studies in AIM 2 utilize bone marrow chimera (BMC) mice to examine TNF-induced IEC B-catenin signaling in radioresistant epithelial populations in DSS colitis mice.
AIM 3 studies examine the role of Nox1 in B-catenin activation using B6->Nox1-/- BMC DSS colitis mice. Together the studies propose that TNF-induced NOX1 stimulates PI3K-mediated B-catenin activation and ISC/PC gene expression to determine crypt responses in IBD. The underlying hypothesis is that inflammation-induced B-catenin signaling enhances epithelial regeneration and induces chronic architectural distortion by increasing ISC and progenitor cell expansion during colitis. The clinical relevance of these studies is great given that we hope to identify novel approaches to IBD therapy and chemoprevention.
The proposal presented plans to examine how patients heal from ulcers (sores) in the bowel during colitis (ulcerative colitis and Crohn's disease). We find that in colitis, small protein molecules made by white blood cells cause stimulation of epithelial cells that line the colon. In this grant we will examine mechanisms that control how inflammation in colitis stimulates epithelial stem cells and increases their risk of turning into colon cancer.
|Goretsky, Tatiana; Bradford, Emily M; Ye, Qing et al. (2018) Beta-catenin cleavage enhances transcriptional activation. Sci Rep 8:671|
|Davoudi, Zahra; Peroutka-Bigus, Nathan; Bellaire, Bryan et al. (2018) Intestinal organoids containing poly(lactic-co-glycolic acid) nanoparticles for the treatment of inflammatory bowel diseases. J Biomed Mater Res A 106:876-886|
|Bradford, Emily M; Ryu, Stacy H; Singh, Ajay Pal et al. (2017) Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease. J Immunol 199:1886-1897|
|Feng, Yongjia; Demehri, Farok R; Xiao, Weidong et al. (2017) Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition. Cell Mol Gastroenterol Hepatol 3:447-468|
|Cohran, Valeria; Managlia, Elizabeth; Bradford, Emily M et al. (2016) Epithelial PIK3R1 (p85) and TP53 Regulate Survivin Expression during Adaptation to Ileocecal Resection. Am J Pathol 186:1837-1846|
|Goretsky, Tatiana; Bradford, Emily M; Ryu, Hyunji et al. (2016) A Cytosolic Multiprotein Complex Containing p85? Is Required for ?-Catenin Activation in Colitis and Colitis-associated Cancer. J Biol Chem 291:4166-77|
|Wen, Yang-An; Li, Xin; Goretsky, Tatiana et al. (2015) Loss of PHLPP protects against colitis by inhibiting intestinal epithelial cell apoptosis. Biochim Biophys Acta 1852:2013-23|
|Wang, Yuhuan; Liu, Xiaoxi; Pijut, Sonja S et al. (2015) The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination. J Lipid Res 56:810-20|
|Managlia, Elizabeth; Katzman, Rebecca B; Brown, Jeffrey B et al. (2013) Antioxidant properties of mesalamine in colitis inhibit phosphoinositide 3-kinase signaling in progenitor cells. Inflamm Bowel Dis 19:2051-60|
|Khan, Mohammad W; Keshavarzian, Ali; Gounaris, Elias et al. (2013) PI3K/AKT signaling is essential for communication between tissue-infiltrating mast cells, macrophages, and epithelial cells in colitis-induced cancer. Clin Cancer Res 19:2342-54|
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