Lymphoepithelial interactions in IBD

描述（由申请方提供）：炎症性肠病（IBD）患者因慢性结肠炎而患结直肠癌（CRC）的风险较高。目前，约有1-2百万美国人患有IBD。2%的溃疡性结肠炎（DC）患者在10年后发生CRC，19%在30年后发生CRC。因此，阐明IBD的致癌机制可能会改善化学预防并提高生存率。最近的分析表明，UC中的异型增生随着炎症的严重程度、持续时间、范围和毒性的增加而增加。本文提供的数据显示，T细胞活化增加了肠隐窝中的Wnt/β-连环蛋白信号传导，这是一种已知调节肠和其他地方干细胞的途径。超过90%的CRC含有Wnt/β-连环蛋白通路基因突变。在45%的UC相关CRC中检测到Wnt/β-连环蛋白信号转导失调。在初步研究中，我们在隐窝上皮细胞的祖细胞群中显示了T细胞诱导的Wnt/β-连环蛋白信号传导。数据表明，在T细胞活化的3小时内，细胞核β-连环蛋白水平和β-连环蛋白靶基因的mRNA增加>200%，随后是增强的c-Myc和CD 44 IHC染色（6小时）和隐窝祖细胞的增殖（BrdU，Ki 67）（12小时）。TNFR 1/2和PI 3 K/Akt信号传导的参与通过分别来自抗CDS处理的TNFR 1/2-/-和Ly-294002（PI 3 K抑制剂）处理的小鼠的隐窝细胞中的Wnt/β-连环蛋白信号传导的40-80%的减少来表明。因此，我们推测上皮TNF受体的参与激活PI 3 K/Akt信号传导，其促进β-连环蛋白的核积累、靶基因表达和隐窝祖细胞中的增殖。目前的建议是通过使用TNFR 1/2和PI 3 K/Akt协同诱导Wnt/β-连环蛋白信号传导来验证这一假设。 TNFR 1/2-/-、TNFR 1-/-、TNFR 2-/-和Aktr-/-小鼠作为骨髓嵌合体（BMC）小鼠的宿主。在BMC小鼠中检查Wnt/β-连环蛋白信号传导将促进我们对IBD中调节淋巴上皮相互作用的机制的理解。

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.