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

基本信息

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
项目类别：
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&apos 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

Abscess Affect Alleles Animal Model Anti-Inflammatory Agents Apoptosis Apoptotic Binding Binding Sites CSF3 gene Cell Differentiation process Cell physiology Cells Chronic Colitis Crohn&apos 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

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项目摘要

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.

项目摘要克罗恩病（CD）和溃疡性结肠炎（UC），两个主要亚型炎症性肠病（IBD），是定义较差的病因的慢性炎症性疾病。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重要的预后端点。此外，目的地侵略性抗炎治疗，很大一部分 CD患者因肠纤维化而产生狭窄，需要手术。那是没有满足的需求替代治疗方案和治疗靶标。整联蛋白结合基质蛋白CCN1 （CYR61）在人类CD和UC患者中进行了更新，并且正在作为关键损伤反应出现协调结肠炎中伤口愈合和组织修复的多个方面的分子。敲击小鼠表达整联蛋白结合有缺陷的CCN1在实验中遭受加剧的发病率和死亡率结肠炎，表现出上皮再生，中性粒细胞持久性和纤维化升高的受损。老鼠与 LGR5+肠干细胞中的CCN1缺失显示实验性结肠炎后的隐窝再生不足，和该基因型的迷你凝结器官表现出异常的LGR5+干细胞增殖。此外，用纯化的CCN1蛋白处理野生型或CCN1突变小鼠，可显着加速粘膜结肠炎的愈合，表明CCN1对IBD具有治疗潜力。基于这些发现，我们假设CCN1在肠道干细胞和受伤后的隐窝再生中起关键作用，并且可能限制肠纤维化。我们将在三个特定目的中审查这一假设：（1）阐明 CCN1在肠再生和干细胞增殖和分化中的功能；（2）评估 CCN1在结肠炎中嗜中性粒细胞清除和体内稳态中的作用；（3）检验以下假设 CCN1可以通过诱导的肌纤维细胞感应或凋亡来限制和逆转肠纤维化。这些研究将对CCN1如何在结肠炎的肠道损伤修复的多个方面进行新见解，并可能导致IBD的新治疗策略和治疗靶标。