DYSREGULATION OF CHOLANGIOCYTE APOPTOSIS BY CYTOKINES

细胞因子对胆管细胞凋亡的失调

• 批准号: 2905020
• 负责人: Tushar Patel
• 金额: $ 12.29万
• 依托单位: SCOTT AND WHITE MEMORIAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2905020
• 关键词: BCL2 gene /protein; animal genetic material tag; apoptosis; athymic mouse; biliary tract; biliary tract neoplasm; carcinogenesis; gastrointestinal epithelium; gene induction /repression; inflammation; interleukin 1; interleukin 6; male; neoplasm /cancer genetics; tissue /cell culture; tumor necrosis factor alpha

Chronic inflammation in gastrointestinal epithelia is characterized by alterations in the cytokine milieu and often predisposes to the development of neoplasia. Primary sclerosing cholangitis, a chronic inflammatory condition affecting the biliary system, is associated with cytokine alterations and the development of cholangiocarcinoma. Dysregulation of apoptosis has recently been implicated as an important contributor to carcinogenesis. We have recently shown that the pro- inflammatory cytokine IL-6 alters the susceptibility of biliary epithelial cells to undergo apoptosis by downregulating Bax, a member of the Bcl-2 family and a dominant tumor suppressor and pro-apoptotic gene. Thus, our HYPOTHESIS is that dysregulation of apoptosis by cytokines is an important mechanism of malignant transformation of biliary epithelia. The SPECIFIC AIMS for this proposal are: 1) To test the hypothesis that pro-inflammatory cytokines such as IL-1, IL-6 and TNFalpha regulate apoptosis by altering the expression or activity of members of the Bcl-2 family of apoptosis regulators; 2) to test the hypothesis that IL-6 alters expression of Bax by a ligand mediated activation of specific signaling pathways resulting in altered gene transcription; and 3) to test the hypothesis that dysregulation of apoptosis by cytokines enhances malignant transformation in biliary epithelial cells due to genotoxic injury. These studies will help to determine the role of cytokines in injury and transformation of biliary epithelia and expand our understanding of the mechanisms mediating malignant transformation in inflammatory states. This information has the promise of ultimately contributing to the development of specific therapies for the cholangiopathies as well as interventions to prevent neoplasia.

胃肠道上皮中的慢性炎症的特征是 细胞因子环境的改变，通常易于 肿瘤的发展。 原发性硬化性胆管炎，一种慢性 影响胆道系统的炎症状况与 细胞因子改变和胆管癌的发展。 凋亡的失调最近被认为是重要的 致癌作用。 我们最近表明， 炎性细胞因子IL-6改变了胆道的敏感性 上皮细胞通过下调Bax，一种成员，通过下调凋亡 Bcl-2家族以及主要的肿瘤抑制剂和促凋亡 基因。 因此，我们的假设是通过 细胞因子是恶性转化的重要机制 胆道上皮。 该建议的具体目的是：1）测试 促炎性细胞因子，例如IL-1，IL-6和 TNFalpha通过改变的表达或活性来调节凋亡 Bcl-2凋亡调节剂家族的成员； 2）测试 假设IL-6通过配体介导的BAX表达 特定信号通路的激活导致基因改变 转录； 3）检验了失调的假设 细胞因子的凋亡增强了胆道中的恶性转化 由于遗传毒性损伤引起的上皮细胞。 这些研究将有助于 确定细胞因子在损伤和转化中的作用 上皮并扩展我们对介导的机制的理解 炎症状态的恶性转化。 此信息具有 最终有助于发展特定的承诺 胆管疾病的疗法以及干预措施 肿瘤。