Lymphoepithelial interactions in IBD

IBD 中的淋巴上皮相互作用

• 批准号: 7173828
• 负责人: Terrence A. Barrett
• 金额: $ 32.9万
• 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/7173828
• 关键词: American; Bone Marrow; Bromodeoxyuridine; CD44 gene; Carcinogenesis Mechanism; Cell Proliferation; Chemoprevention; Chimera organism; Chronic; Colitis; Colorectal Cancer; Data; Dysplasia; Epithelial; Epithelial Cells; Gene Expression; Gene Targeting; Genes; Immunohistochemistry; Inflammation; Inflammatory Bowel Diseases; Intestines; LY294002; Mediating; Messenger RNA; Mus; Mutation; Nuclear; PI3K/AKT; Pathway interactions; Patients; Play; Population; Proteins; Research Personnel; Risk; Role; Severities; Signal Transduction; Staining method; Stains; Stem cells; T-Cell Activation; T-Lymphocyte; TNFRSF1A gene; TNFRSF1B gene; Testing; Tumor Necrosis Factor Receptor; Ulcerative Colitis; beta catenin; c-myc Genes; crypt cell; improved; inhibitor/antagonist; intestinal crypt; knockout gene; progenitor; programs; response

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(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100-200万美国人患有IBD。在溃疡性结肠炎(DC)患者中，2%的患者在10年后发生CRC，19%的患者在30年后发生。因此，阐明IBD的致癌机制可以改善化学预防，提高存活率。最近的分析表明，UC的异型增生随着炎症的严重程度、持续时间、程度和软化程度的增加而增加。这里提供的数据表明，T细胞的激活增加了肠道隐窝中的Wnt/p-catenin信号，这是一条已知的调节肠道和其他地方的干细胞的途径。90%以上的结直肠癌中存在Wnt/p-catenin途径基因突变。45%的UC相关结直肠癌中检测到Wnt/p-catenin信号转导异常。在初步研究中，我们展示了T细胞在隐窝上皮细胞的祖细胞群中诱导Wnt/β-catenin信号转导。数据表明，在T细胞激活的3h内，核β-catenin水平和p-catenin靶基因的mRNA增加了200%，随后是c-Myc和CD44IHC染色增强(6h)和隐窝祖细胞增殖(BrdU，Ki67)(12h)。TnFRI/2-/-和Ly-294002(PI3K抑制剂)处理的小鼠隐窝细胞中的Wnt/p-catenin信号分别减少了40-80%，提示参与了TnFR1/2和PI3K/Akt信号转导。因此，我们推测上皮性肿瘤坏死因子受体的结合激活了PI3K/Akt信号通路，从而促进了隐窝前体细胞中β-连环蛋白的核积聚、靶基因的表达和增殖。目前的建议验证了这样的假设，即TNFR1/2和PI3K/Akt合作通过使用 以TNFR1/2-/-、TNFR1-/-、TNFR2-/-和Aktr-/-小鼠作为骨髓嵌合体(BMC)小鼠的宿主。在骨髓基质细胞小鼠中检测Wnt/β-catenin信号将促进我们对IBD淋巴上皮相互作用的调控机制(S)的理解。