Lymphoepithelial interactions in IBD

描述（由申请人提供）：炎症性肠病（IBD）患者是由慢性结肠炎引起的结直肠癌（CRC）的高风险患者。目前，有1- 200万美国人患有炎症性肠病。溃疡性结肠炎（DC）患者10年后发生CRC的比例为2%，30年后发生CRC的比例为19%。因此，阐明IBD的癌变机制可以改善化学预防和提高生存率。最近的分析表明UC的不典型增生随着炎症的严重程度、持续时间、程度和软骨性的增加而增加。本文提供的数据表明，T细胞激活会增加肠隐窝中的Wnt/p-catenin信号，这是一种已知的调节肠道和其他地方干细胞的途径。超过90%的结直肠癌包含Wnt/p-catenin通路基因突变。在45%的uc相关CRC中检测到失调的Wnt/p-catenin信号。在初步研究中，我们发现T细胞诱导的Wnt/ β -连环蛋白信号传导在隐窝上皮细胞的祖细胞群中。数据显示，在T细胞活化3h内，细胞核β -catenin水平和p-catenin靶基因mRNA增加了bb0 - 200%，随后隐窝祖细胞c-Myc和CD44 IHC染色（6h）和增殖（BrdU, Ki67） （12h）增强。抗cdss处理的TNFRI/2-/-和Ly-294002 （PI3K抑制剂）处理的小鼠隐窝细胞中Wnt/p-catenin信号分别减少40-80%，表明TNFR1/2和PI3K/Akt信号通路参与。因此，我们假设上皮TNF受体的参与激活PI3K/Akt信号，从而促进β -连环蛋白的核积累、靶基因的表达和隐窝祖细胞的增殖。本研究通过使用TNFR1/2和PI3K/Akt共同诱导Wnt/ β -catenin信号传导，验证了TNFR1/2和PI3K/Akt共同诱导Wnt/ β -catenin信号传导的假设

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.