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: 8893972
• 负责人: Terrence A. Barrett
• 金额: $ 30.84万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893972
• 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; Focal Infection; 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 predictors; clinical remission; clinically relevant; colitis associated cancer; healing; in vivo; kinase inhibitor; member; myoinositol; novel; novel strategies; radioresistant; 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.

描述（由申请人提供）：炎症性肠病（IBD）中粘膜愈合的诱导与住院和手术减少有关。粘膜屏障的愈合需要控制破坏性的炎症反应，并通过增强和产生新的加密结构来恢复上皮屏障。 尽管很明显，诱导Wnt/b - - - - - - 催化蛋白激活是肠干（ISC）和祖细胞（PC）激活的关键因素，但很少有研究人员研究了结肠炎中B- - - - - - - - - 催化剂激活的调节，其中粘膜愈合和炎症引起的炎症诱导的发育不全是主要的临床问题。在上一项奖项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-catenin的Akt磷酸化增加。本提案利用一种新型的遗传模型来减少结肠炎期间结肠肠上皮细胞（IEC）中的PI3K信号传导。给定DSS结肠炎的VILCRE/PIK3R1FL/FL小鼠已经产生的数据表明，PI3K介导的B-catenin激活在伤口愈合中起主要作用。 DSS结肠炎的急性和慢性形式将在VILCRE/PIK3R1FL/FL小鼠中产生 AIM 1中的VIVO研究检查了IEC 1A类PI3K在粘膜愈合，B-catenin激活和ISC/PC基因表达（使用新型肠层培养物）中的作用。 AIM 2的研究利用骨髓嵌合体（BMC）小鼠在DSS结肠炎小鼠的放射性上皮种群中检查TNF诱导的IEC B-catenin信号传导。 AIM 3研究研究了使用B6-> NOX1 - / - BMC DSS结肠炎小鼠NOX1在B-catenin激活中的作用。研究共同提出，TNF诱导的NOX1刺激PI3K介导的B-catenin激活和ISC/PC基因表达，以确定IBD中的隐窝反应。潜在的假设是，炎症诱导的B-catenin信号传导可增强上皮再生，并通过增加结肠炎过程中的ISC和祖细胞扩张来诱导慢性建筑失真。鉴于我们希望确定IBD疗法和化学预防的新方法，这些研究的临床相关性很棒。