Integrin-mediated matricellular signaling in experimental colitis

实验性结肠炎中整合素介导的基质细胞信号传导

• 批准号: 9912136
• 负责人: LESTER F LAU
• 金额: $ 43.17万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912136
• 关键词: Abscess; Affect; Alleles; Animal Model; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Binding; Binding Sites; CSF3 gene; Cell Differentiation process; Cell physiology; Cells; Chronic; Colitis; Crohn' s disease; Disease; Epithelial; Epithelium; Etiology; Exhibits; Fibrosis; Genotype; Homeostasis; Hospitalization; Human; Impairment; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injections; Injury; Integrin Binding; Integrin alphaV; Integrin alphaVbeta3; Integrins; Interleukin-17; Intestinal Fibrosis; Intestines; Investigation; Knock-in Mouse; LGR5 gene; Lamina Propria; Lead; Macrophage-1 Antigen; Mediating; Morbidity - disease rate; Mucous Membrane; Mus; Mutant Strains Mice; Mutation; Myofibroblast; Natural regeneration; Operative Surgical Procedures; Opsonin; Organoids; Pathway interactions; Patients; Play; Process; Proteins; Resolution; Role; Series; Signal Pathway; Signal Transduction; Sodium Dextran Sulfate; TNF gene; Testing; Therapeutic; Ulcerative Colitis; United States; Wild Type Mouse; alternative treatment; base; cell type; colonic crypt; dextran sulfate sodium induced colitis; epithelium regeneration; experience; healing; injury and repair; insight; interleukin-23; intestinal epithelium; intestinal injury; mortality; mouse model; mutant; neutrophil; novel; novel therapeutics; progenitor; prognostic; programs; receptor; repaired; response; response to injury; senescence; stem cell proliferation; stem cells; therapeutic target; tissue repair; traditional therapy; treatment strategy; wound healing; wound injury

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.

项目概要 克罗恩病（CD）和溃疡性结肠炎（UC）是炎症性肠病（IBD）的两种主要亚型， 是病因不明的慢性炎症性疾病，传统疗法主要集中于治疗。 改善炎症，尽管最近的研究表明粘膜愈合是一个重要的因素 此外，尽管进行了积极的抗炎治疗，仍有很大比例的患者出现预后不良。 CD 患者因肠纤维化而出现狭窄并需要手术，因此，对药物的需求尚未得到满足。 替代治疗方案和治疗靶点整合素结合基质细胞蛋白 CCN1。 (CYR61) 在患有 CD 和 UC 的人类患者中表达上调，并且正在成为一种关键的损伤反应 协调 Knockin 小鼠伤口愈合和组织修复的多个方面的分子。 表达整合素结合缺陷的 CCN1 加剧了实验中的发病率和死亡率 结肠炎，显示上皮再生受损、中性粒细胞持久性和纤维化程度升高。 Lgr5+肠干细胞中的Ccn1缺失显示实验性结肠炎后隐窝再生不足， 具有该基因型的小肠类器官表现出异常的 Lgr5+ 干细胞增殖。 用纯化的 CCN1 蛋白治疗野生型或 Ccn1 突变小鼠显着加速粘膜 结肠炎的治愈，表明 CCN1 对 IBD 的治疗潜力。 坚持CCN1在肠道干细胞和损伤后隐窝再生中发挥关键作用，并且 可能会限制肠道纤维化。我们将从三个具体目的来仔细研究这一假设：（1）阐明 (2)评价CCN1在肠道再生和干细胞增殖分化中的功能； CCN1 在结肠炎中性粒细胞清除和稳态中的作用；以及 (3) 检验以下假设： CCN1可以通过诱导肌成纤维细胞衰老或凋亡来限制和逆转肠纤维化。 研究将对 CCN1 如何作用于结肠炎肠道损伤修复的多个方面产生新的见解， 并可能为 IBD 带来新的治疗策略和治疗靶点。