Role of Corticotropin Releasing Hormone in Intestinal Inflammation

 描述(申请人提供)：促肾上腺皮质激素释放激素(CRH或CRF)是下丘脑ACTH释放的主要调节因子。我们以前的研究表明，外周CRH及其家族成员urocortin 2(Ucn2)和urocortin 3(Ucn3)通过与CRH受体2(CRHR2)结合并激活与结肠炎和IBD后粘膜愈合有关的重要途径，包括细胞增殖、迁移和伤口愈合，参与肠道炎症。这一应用将验证CRHR2激活通过与结肠上皮细胞和结肠成纤维细胞相互作用来刺激增殖、促进上皮伤口愈合、抑制细胞凋亡并刺激人结肠成纤维细胞释放细胞因子和生长因子，从而协调结肠炎后粘膜愈合的新假说。我们还将研究CRHR2的功能异构体，CRHR2α，CRHR2β，及其最近鉴定的可溶小鼠切片变体sCRHR2α的作用。以下目标将解决这些假设。目的1利用CRHR2受体拮抗剂CRHR2-/-和肠上皮细胞特异性CRHR2-/-(CRHR2LoxP/loxP)小鼠，研究CRHR2及其配体CRH、Ucn2和Ucn3在结肠炎后粘膜愈合中的作用。目的2将验证CRHR2激活促进粘膜修复重编程的假说，并研究涉及的潜在信号通路，特别是IL-6/STAT3，Akt和EGFR通路在人结肠上皮细胞上的表达。目的通过从CRHR2-/-小鼠和肠上皮细胞特异性CRHR2-/-小鼠分离的结肠成纤维细胞和从IBD患者分离的人肠成纤维细胞，研究CRHR2信号在人结肠成纤维细胞在粘膜愈合中的作用。这些研究将促进我们对IBD发病机制的理解，并明确CRH信号在这一重要疾病组中的作用和机制。

 DESCRIPTION (provided by applicant): Corticotropin-releasing hormone (CRH or CRF) is the major hypothalamic regulator of ACTH release. Our previous studies showed that peripheral CRH and its family members Urocortin 2 (Ucn2) and Urocortin 3 (Ucn3) participate in intestinal inflammation by binding to CRH receptor 2 (CRHR2) and activating important pathways linked to mucosal healing following colitis and IBD, including cell proliferation, and migration and wound healing. This application will test the novel hypothesis that CRHR2 activation coordinates mucosal healing following colitis by interacting with colonic epithelial cells and colonic fibroblats to stimulate proliferation, enhance epithelial wound healing, inhibit apoptosis and stimulate release of cytokines and growth factors from human colonic fibroblasts. The role of the functional CRHR2 isoforms, CRHR2α, CRHR2β, and its recently characterized soluble mouse slice variant, sCRHR2α will also be examined. The following aims will address these hypotheses. Aim 1 will establish the role of CRHR2 and its ligands CRH, Ucn2 and Ucn3 in mucosal healing following colitis using specific CRHR2 receptor antagonists, CRHR2 -/- and intestinal epithelial cell specific CRHR2-/- (CRHR2LoxP/LoxP) mice. Aim 2 will examine the hypothesis that CRHR2 activation stimulates mucosal healing re-programming and investigate the underlying signaling pathways involved, with particular focus on the IL-6/STAT3, Akt and EGFR pathways on human colonic epithelial cells. Aim 3 will address the role of CRHR2 signaling on human colonic fibroblasts in mucosal healing using colonic fibroblasts isolated from CRHR2-/- and intestinal epithelial cell specific CRHR2-/- mice as well as human intestinal fibroblasts isolated from IBD patients. These studies should advance our understanding on the pathogenesis of IBD and define the role and mechanisms of CRH signaling in this important group of diseases.