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.

项目总结