Regulation of Intestinal Stem Cell Activation in Colitis

结肠炎中肠道干细胞激活的调节

• 批准号: 8441348
• 负责人: Terrence A. Barrett
• 金额: $ 32.7万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441348
• 关键词: Acute; Attenuated; Award; Biopsy; Bone Marrow; Cell Culture Techniques; Cell Line; Chemoprevention; Chicago; Chimera organism; Chronic; Clinical; Clinical Trials; Colitis; Colon; Colon Carcinoma; Colorectal Cancer; Crohn' s disease; Data; Dysplasia; Enrollment; Epithelial; Epithelial Cells; Figs - dietary; Gene Expression; Generations; Genes; Genetic Models; Goblet Cells; Grant; Healed; Hospitalization; In Vitro; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Leukocytes; Malignant Neoplasms; Mediating; Modeling; Monoclonal Antibodies; Mucositis; Mus; Mutate; Natural regeneration; Operative Surgical Procedures; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Population; Proteins; Publishing; Reactive Oxygen Species; Regulation; Research Personnel; Residual state; Risk; Role; Sampling; Severities; Severity of illness; Signal Transduction; Sodium Dextran Sulfate; Stem cells; Structure; Study models; Systemic infection; TNFRSF1A gene; Testing; Time; Tissues; Tumor Necrosis Factor-alpha; Ulcer; Ulcerative Colitis; Universities; Wound Healing; base; carcinogenesis; clinical remission; clinically relevant; colitis associated cancer; healing; in vivo; kinase inhibitor; member; myoinositol; novel; novel strategies; repaired; response; stem; therapy outcome

DESCRIPTION (provided by applicant): Induction of mucosal healing in inflammatory bowel disease (IBD) is associated with reduced hospitalizations and surgeries. Healing of the mucosal barrier requires control of the destructive inflammatory response as well as restitution of the epithelial barrier through enhanced proliferation and generation of new crypt structures. Although it is clear that induction of Wnt/B-catenin activation is a key factor in intestinal stem ell (ISC) and progenitor cell (PC) activation, there are few researchers that examine the regulation of B-catenin activation in colitis where mucosal healing and inflammation-induced dysplasia are major clinical concerns. Studies performed during the prior award period demonstrated that Akt phosphorylation of B-catenin increases in ISCs during colitis and colitis-induced cancer. The present proposal makes use of a novel genetic model for reducing PI3K signaling in colonic intestinal epithelial cells (IEC) during colitis. Data already produced in VilCre/pik3r1fl/fl mice given DSS colitis suggest that PI3K-mediated B-catenin activation plays a major role in wound healing. Acute and chronic forms of DSS colitis will be generated in VilCre/pik3r1fl/fl mice for in vivo studies in AIM 1 to examine the role of IEC class 1A PI3K in mucosal healing, B-catenin activation and ISC/PC gene expression (using novel enteroid cultures). Studies in AIM 2 utilize bone marrow chimera (BMC) mice to examine TNF-induced IEC B-catenin signaling in radioresistant epithelial populations in DSS colitis mice. AIM 3 studies examine the role of Nox1 in B-catenin activation using B6->Nox1-/- BMC DSS colitis mice. Together the studies propose that TNF-induced NOX1 stimulates PI3K-mediated B-catenin activation and ISC/PC gene expression to determine crypt responses in IBD. The underlying hypothesis is that inflammation-induced B-catenin signaling enhances epithelial regeneration and induces chronic architectural distortion by increasing ISC and progenitor cell expansion during colitis. The clinical relevance of these studies is great given that we hope to identify novel approaches to IBD therapy and chemoprevention. PUBLIC HEALTH RELEVANCE: The proposal presented plans to examine how patients heal from ulcers (sores) in the bowel during colitis (ulcerative colitis and Crohn's disease). We find that in colitis, small protein molecules made by white blood cells cause stimulation of epithelial cells that line the colon. In this grant we will examine mechanisms that control how inflammation in colitis stimulates epithelial stem cells and increases their risk of turning into colon cancer.

描述(由申请人提供)：炎症性肠病(IBD)的粘膜愈合诱导与减少住院和手术有关。粘膜屏障的修复需要控制破坏性的炎症反应，并通过促进增殖和产生新的隐窝结构来恢复上皮屏障。虽然Wnt/B-catenin激活的诱导是肠干细胞(ISC)和祖细胞(PC)激活的关键因素，但很少有研究人员研究B-catenin激活在结肠炎中的调节作用，在结肠炎中，粘膜愈合和炎症诱导的异型增生是主要的临床问题。在之前的获奖期间进行的研究表明，在结肠炎和结肠炎诱导的癌症期间，B-连环蛋白的Akt磷酸化增加了ISCs。目前的建议利用一种新的遗传模型来减少结肠炎期间结肠肠上皮细胞(IEC)中的PI3K信号。在DSS结肠炎的VilCre/pik3r1fl/fl小鼠中已经产生的数据表明，PI3K介导的B-连环蛋白激活在伤口愈合中起主要作用。将在VilCre/pik3r1fl/fl小鼠中产生急性和慢性DSS结肠炎 目的1研究IEC 1A型PI3K在黏膜愈合、B-连环蛋白激活和ISC/PC基因表达中的作用(使用新的肠样培养)。目的研究目的2利用骨髓嵌合体(BMC)小鼠检测肿瘤坏死因子诱导的DSS结肠炎小鼠放射抵抗上皮群中IEC B-catenin信号转导。目的利用B6-&gt；Nox1-/-BMC DSS结肠炎小鼠模型，研究Nox1在B-连环蛋白活化中的作用。综上所述，研究表明，肿瘤坏死因子诱导的NOX1刺激PI3K介导的B-连环蛋白激活和ISC/PC基因的表达来确定IBD的隐窝反应。潜在的假设是，炎症诱导的B-连环蛋白信号增强了结肠炎期间的上皮再生，并通过增加ISC和前体细胞的扩张而诱导慢性结构扭曲。鉴于我们希望确定IBD治疗和化学预防的新方法，这些研究的临床意义很大。 公共卫生相关性：该提案提出了检查患者在结肠炎(溃疡性结肠炎和克罗恩病)期间如何治愈肠道溃疡(溃疡)的计划。我们发现，在结肠炎中，由白细胞制造的小蛋白分子会刺激结肠内的上皮细胞。在这项拨款中，我们将研究控制结肠炎炎症如何刺激上皮干细胞并增加其转化为结肠癌风险的机制。