Role of CRH receptor 2 in mucosal healing during colitis

描述(申请人提供)：克罗恩病(CD)和溃疡性结肠炎(UC)，统称为炎症性肠病(IBD)，是慢性复发性胃肠道炎症性疾病。虽然IBD的病因尚不完全清楚，但它被认为部分是由粘膜上皮的缺陷所介导的。促肾上腺皮质激素释放激素(CRH)家族包括中枢和外周合成的激素/肽，影响包括肠道在内的许多器官的功能。CRH受体2在结肠炎急性期的激活可促进炎症反应，在慢性结肠炎时可促进粘膜修复。由于粘膜愈合是治疗结肠炎的理想终点，我们将研究CRHR2信号在结肠粘膜中的特定调节是否可以限制炎症或促进上皮屏障的恢复。这项奖学金提案的总体目标是：(1)展示CRHR2及其配体在结肠炎相关粘膜愈合中的作用；(2)确定CRHR2受体/配体系统刺激结肠上皮细胞愈合相关反应的分子机制(S)。为了实现这些目标，我们将研究CRHR2及其配体CRH、urocortin 2和urocortin 3在葡聚糖硫酸钠(DSS)结肠炎粘膜愈合期小鼠结肠中的表达谱。我们还将评估DSS治疗的小鼠在给予选择性CRHR2拮抗剂后的结肠细胞增殖、凋亡和炎症细胞因子水平，以及CRHR2基因敲除小鼠和条件性肠上皮细胞特异性CRHR2基因敲除小鼠的水平。此外，我们将测试肠上皮细胞中IL-6/STAT3活性介导DSS治疗的小鼠结肠炎后依赖CRHR2的粘膜愈合的假设，以及来自IBD患者和匹配对照组的结肠粘膜活检。这项奖学金提案涉及一系列创新方法的结合，利用肠道炎症的动物模型以及来自IBD患者的人体组织。赞助团队及其实验室在拟议方法方面的实力和专业知识为开展研究提供了独特的指导环境，而培训计划是实现申请人作为独立调查人员取得成功的长期目标不可或缺的一部分。此外，由于对结肠上皮CRH信号在粘膜修复中的作用知之甚少，拟议的AIMS的发现可能为促进IBD粘膜愈合的靶向药物方法创造潜在的机会。

DESCRIPTION (provided by applicant): Crohn's Disease (CD) and Ulcerative Colitis (UC), collectively known as Inflammatory Bowel Disease (IBD), are chronic relapsing inflammatory disorders of the gastrointestinal tract. While the etiology of IBD is not fully understood, it is thought to be mediated in part by a defect in the mucosal epithelium. The corticotropin- releasing hormone (CRH) family includes hormones/peptides synthesized both centrally and peripherally, affecting the function of many organs, including the intestine. Activation of CRH receptor 2 in the colonic mucosa has been shown to both promote inflammation during the acute phase of colitis and enhance mucosal repair during chronic colitis. As mucosal healing is a desired therapeutic endpoint in the treatment of colitis, we will investigate whether specific modulation of CRHR2 signaling in the colonic mucosa can limit inflammation or promote restoration of the epithelial barrier. The overall objectives of this fellowship proposal are to: () demonstrate the role of CRHR2 and its ligands in colitis-associated mucosal healing and (2) identify the molecular mechanism(s) by which the CRHR2 receptor/ligand system stimulates healing-associated responses in colonic epithelial cells. To achieve these goals, we will characterize the expression profiles of CRHR2 and its ligands CRH, Urocortin 2 and Urocortin 3 in the mouse colon during the mucosal healing phase of dextran sodium sulfate (DSS) colitis. We will also evaluate colonic cell proliferation, apoptosis and inflammatory cytokine levels in DSS-treated mice following administration of a selective CRHR2 antagonist, in CRHR2 knockout mice and in conditional intestinal epithelial cell-specific CRHR2 knockout mice. Furthermore, we will test the hypothesis that IL-6/STAT3 activity in intestinal epithelial cells mediates CRHR2-dependent mucosal healing following colitis in DSS-treated mice as well as colonic mucosal biopsies from IBD patients and matched controls. This fellowship proposal involves a combination of innovative approaches utilizing both an animal model of intestinal inflammation as well as human tissues from IBD patients. The strength and expertise of the sponsorship team and their laboratories in the proposed approaches provide a unique mentoring environment to conduct the studies, and the training plan is integral to achieving the applicant's long-term goal to succeed as an independent investigator. Furthermore, as very little is known regarding the role of colonic epithelial CRH signaling in mucosal repair, findings from the proposed aims could create potential opportunity for targeted pharmaceutical approaches to enhance mucosal healing in IBD.