Integrin-mediated matricellular signaling in experimental colitis

项目总结 克罗恩病(CD)和溃疡性结肠炎(UC)，炎症性肠病(IBD)的两个主要亚型， 是病因不明的慢性炎症性疾病。传统疗法的重点是 炎症的改善，尽管最近的研究表明粘膜愈合是一个重要的 预测终点。此外，尽管进行了积极的抗炎治疗，但仍有相当大比例的 CD患者因肠道纤维化而出现狭窄，需要手术治疗。因此，有一种未得到满足的需求 可供选择的治疗方案和治疗目标。整合素结合的基质细胞蛋白CCN1 (CYR61)在CD和UC患者中表达上调，并正在成为一种关键的损伤反应 在结肠炎中协调伤口愈合和组织修复的多方面的分子。诺金小鼠 表达整合素结合缺陷的CCN1会加重实验性大鼠的发病率和死亡率 结肠炎，表现为上皮再生受损，中性粒细胞持续存在，纤维化加重。小鼠带有 Lgr5肠道干细胞中CCN1缺失显示实验性结肠炎后隐窝再生不足， 该基因的迷你肠道类器官表现出异常的Lgr5干细胞增殖。此外， 纯化的CCN1蛋白治疗野生型或CCN1突变小鼠显著促进粘膜 结肠炎痊愈，提示CCN1对IBD有治疗潜力。基于这些发现，我们 假设CCN1在肠干细胞和损伤后的腺体再生中起关键作用，以及 可能会限制肠道纤维化。我们将在三个具体目标上仔细研究这一假设：(1)阐明 CCN1在肠道再生和干细胞增殖分化中的作用；(2)评价 CCN1在结肠炎中性粒细胞清除和稳态中的作用；以及(3)检验假设 CCN1可通过诱导肌成纤维细胞衰老或凋亡来抑制和逆转肠纤维化。这些 研究将对CCN1如何在结肠炎肠道损伤修复的多个方面发挥作用提供新的见解。 并可能为IBD带来新的治疗策略和治疗靶点。

PROJECT SUMMARY Crohn’s disease (CD) and ulcerative colitis (UC), two major subtypes of inflammatory bowel disease (IBD), are chronic inflammatory disorders of poorly defined etiology. Traditional therapies have focused on amelioration of inflammation, although recent studies have indicated that mucosal healing is an important prognostic endpoint. Moreover, despite aggressive anti-inflammatory treatment, a significant percentage of CD patients develop strictures from intestinal fibrosis and require surgery. Thus, there is an unmet need for alternative treatment options and therapeutic targets. The integrin-binding matricellular protein CCN1 (CYR61) is upregulated in human patients with CD and UC, and is emerging as a key injury response molecule that coordinates multiple aspects of wound healing and tissue repair in colitis. Knockin mice expressing integrin-binding defective CCN1 suffer exacerbated morbidity and mortality in experimental colitis, showing impaired epithelial regeneration, neutrophil persistence, and elevated fibrosis. Mice with Ccn1 deletion in Lgr5+ intestinal stem cells show deficient crypt regeneration following experimental colitis, and mini-gut organoids with this genotype exhibit aberrant Lgr5+ stem cell proliferation. Furthermore, treatment of wild type or Ccn1 mutant mice with purified CCN1 protein significantly accelerates mucosal healing from colitis, suggesting a therapeutic potential of CCN1 for IBD. Based on these findings, we hypothesize that CCN1 plays critical roles in intestinal stem cells and crypt regeneration after injury, and may limit intestinal fibrosis. We will scrutinize this hypothesis in three specific aims: (1) to elucidate the functions of CCN1 in intestinal regeneration and stem cell proliferation and differentiation; (2) to evaluate the role of CCN1 in neutrophil clearance and homeostasis in colitis; and (3) to test the hypothesis that CCN1 can limit and reverse intestinal fibrosis by inducing myofibroblast senescence or apoptosis. These studies will yield new insights into how CCN1 acts on multiple aspects of intestinal injury repair in colitis, and may lead to new treatment strategies and therapeutic targets for IBD.