Lymphoepithelial interactions in IBD

IBD 中的淋巴上皮相互作用

• 批准号: 7104345
• 负责人: Terrence A. Barrett
• 金额: $ 33.88万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104345
• 关键词: T lymphocyte; biological signal transduction; bone marrow transplantation; cadherins; cancer risk; carcinogenesis; cell nucleus; cell proliferation; colitis; colorectal neoplasms; cytokine receptors; enzyme activity; gastrointestinal epithelium; genetically modified animals; immunocytochemistry; inflammatory bowel diseases; intestinal villi; kinase inhibitor; laboratory mouse; leukocyte activation /transformation; phosphatidylinositol 3 kinase; receptor expression; tumor necrosis factor alpha; western blottings

DESCRIPTION (provided by applicant): Patients with inflammatory bowel disease (IBD) are at high risk of colorectal cancer (CRC) arising from chronic colitis. Currently, 1-2 million Americans suffer from IBD. CRC occurs in 2% of patients with ulcerative colitis (DC) after 10 years and 19% after 30 years. Therefore, elucidating mechanisms of carcinogenesis in IBD may improve chemoprevention and enhance survival. Recent analyses suggest dysplasia in UC increases with increasing severity, duration, extent and chonicity of inflammation. Data presented here show that T cell activation increases Wnt/p-catenin signaling in intestinal crypts, a pathway known to regulate stem cells in the intestine and elsewhere. Over 90% of CRC contain mutations in Wnt/p-catenin pathway genes. Dysregulated Wnt/p-catenin signaling is detected in 45% of UC-associated CRC. In preliminary studies, we show T cell-induced Wnt/beta-catenin signaling in progenitor populations of crypt epithelial cells. Data indicate that within 3h of T cell activation, nuclear beta-catenin levels and mRNA for p-catenin target genes increase by >200% followed by enhanced c-Myc and CD44 IHC staining (6h) and proliferation (BrdU, Ki67) (12h) of crypt progenitor cells. Involvement of TNFR1/2 and PI3K/Akt signaling was suggested by 40-80% reduction of Wnt/p-catenin signaling in crypt cells from anti-CDS-treated TNFRI/2-/- and Ly-294002 (PI3K inhibitor)-treated mice respectively. Thus, we postulate that engagement of epithelial TNF receptor activates PI3K/Akt signaling which promotes nuclear accumulation of beta-catenin protein, target gene expression and proliferation in crypt progenitor cells. The current proposal tests the hypothesis that TNFR1/2 and PI3K/Akt cooperate to induce Wnt/beta-catenin signaling by using TNFR1/2-/-, TNFR1-/-, TNFR2-/- and Aktr-/- mice as hosts for bone marrow chimera (BMC) mice. Examination of Wnt/beta-catenin signaling in BMC mice will advance our understanding of mechanism(s) regulating lymphoepithelial interactions in IBD.

描述（由申请人提供）：炎性肠病患者（IBD）患有大肠癌（CRC）的高风险是由慢性结肠炎引起的。目前，有1-200万美国人患有IBD。 CRC发生在10年后2％的溃疡性结肠炎（DC）患者中发生，30年后19％。因此，阐明IBD癌变的机制可以改善化学预防并提高生存率。最近的分析表明，UC的发育不良随着炎症的严重程度，持续时间，程度和诵经性的增加而增加。此处提供的数据表明，T细胞激活增加了肠道隐窝中的Wnt/p-catenin信号传导，这是一种已知的途径，可调节肠道和其他地方的干细胞。超过90％的CRC包含Wnt/p-catenin途径基因中的突变。在45％的UC相关CRC中检测到Wnt/P-catenin信号失调。在初步研究中，我们显示了T细胞诱导的隐窝上皮细胞祖细胞中T细胞诱导的Wnt/β-catenin信号传导。数据表明，在T细胞激活的3H中，P-catenin靶基因的核β-catenin水平和mRNA在加密祖细胞的C-MYC和CD44 IHC染色（6H）和增殖（BRDU，KI67）（12H）（12H）（12H）（12H）的C-Myc和CD44 IHC染色（6H）（12H）中增加。 TNFR1/2和PI3K/AKT信号的参与通过抗CDS处理的TNFRI/2-/ - / - 和LY-294002（PI3K抑制剂）造成的小鼠的wnt/p-catenin信号传导的参与提出了40-80％。因此，我们假设上皮TNF受体的参与激活PI3K/AKT信号传导，该信号促进了β-catenin蛋白的核积累，靶基因表达和地穴祖细胞中的增殖。当前的提案检验了TNFR1/2和PI3K/AKT合作以诱导Wnt/beta-catenin信号传导的假设 TNFR1/2 - / - ，TNFR1 - / - ，TNFR2 - / - 和Aktr - / - 小鼠作为骨髓嵌合体（BMC）小鼠的宿主。 BMC小鼠中Wnt/β-catenin信号传导的检查将提高我们对调节IBD淋巴皮相互作用的机制的理解。