Regulation of Intestinal Stem Cell Activation in Colitis

描述（由申请人提供）：炎症性肠病（IBD）的粘膜愈合诱导与减少住院和手术有关。粘膜屏障的愈合需要控制破坏性炎症反应，并通过增强增殖和产生新的隐窝结构来恢复上皮屏障。虽然很明显，诱导Wnt/B-catenin活化是肠干细胞（ISC）和祖细胞（PC）活化的关键因素，但很少有研究人员研究B-catenin在结肠炎中的活化调节，结肠炎的粘膜愈合和炎症诱导的发育不良是主要的临床问题。先前的研究表明，在结肠炎和结肠炎诱导的癌症期间，Akt磷酸化的B-catenin在ISCs中增加。本提案利用一种新的遗传模型来减少结肠炎期间结肠肠上皮细胞（IEC）中的PI3K信号。在给予DSS结肠炎的VilCre/pik3r1fl/fl小鼠中已经获得的数据表明，pi3k介导的b -连环蛋白激活在伤口愈合中起主要作用。在VilCre/pik3r1fl/fl小鼠中会产生急性和慢性形式的DSS结肠炎

DESCRIPTION (provided by applicant): 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.