IMMUNE-MEDIATED BILE DUCT INJURY IN BILIARY ATRESIA

胆道闭锁中免疫介导的胆管损伤

• 批准号: 6091826
• 负责人: Sheri M. Krams
• 金额: $ 7.82万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6091826
• 关键词: RNase protection assay; T lymphocyte; apoptosis; biliary atresia; cell migration; chemokine; cytokine receptors; gene expression; human subject; infant human (0-1 year); microarray technology; pathologic process

DESCRIPTION (adapted from the application) Biliary atresia is a very serious disease of the newborn in which there is an obliteration or discontinuity of the biliary system. The incidence of this neonatal cholestatic disorder is 1 in 10,000 live births worldwide. If left untreated biliary atresia leads to end-stage liver disease with a median survival of eight months after birth. Thus, biliary atresia is the most common indication for pediatric liver transplantation. The etiology remains unknown and there is little information on disease progression. We have obtained preliminary data to explain the localization of specific lymphocyte subsets to biliary atresia liver. Furthermore, we have identified candidate mediators of cholangiocyte cell death. The objective of this research is to elucidate the immune mediated events which lead to lymphocyte accumulation in the liver and destruction of the bile ducts. In Specific Aim 1 we propose to establish the expression pattern of the chemokines in biliary atresia liver and confirm that lymphocytes with receptors for these chemokines traffic to the liver. Liver tissue from patients with biliary atresia will be analyzed by ribonuclease protection assays and immunohistochemical staining to identify specific chemokines as well as their cellular source and the T cell subsets bearing receptors for these chemokines. Specific Aim 2 will establish if apoptosis is involved in the bile duct obliteration in biliary atresia. Specifically, we will determine the extent and localization of apoptotic cells in biliary atresia liver. In addition, we will examine biliary atresia liver for the presence of well-defined mediators of apoptosis and determine the subsets of infiltrating cells which express these mediators. In Specific Aim 3 we will utilize cDNA microarray strategies to compare gene expression patterns in biliary atresia at early and late stages of disease as well as to other cholestatic liver pathologies. This approach will offer opportunities to identify known and novel genes which participate in the pathogenesis of biliary atresia. We anticipate that these studies will provide unique insights into the pathogenesis of biliary atresia and form the groundwork for future studies related to this severe and enigmatic liver disease.

描述（改编自应用程序） 胆道闭锁是一种非常严重的新生儿疾病。 胆道系统的闭塞或中断。这种情况的发生 新生儿胆汁淤积性疾病占全世界活产婴儿的万分之一。如果离开 未经治疗的胆道闭锁会导致终末期肝病，中位数为 出生后存活八个月。因此，胆道闭锁是最常见的 小儿肝移植的指征。病因尚不清楚 并且关于疾病进展的信息很少。我们已经获得了 初步数据解释特定淋巴细胞亚群的定位 肝脏胆道闭锁。此外，我们还确定了候选调解员 胆管细胞死亡。这项研究的目的是阐明 免疫介导的事件导致淋巴细胞在肝脏中积聚， 胆管的破坏。在具体目标 1 中，我们建议建立 趋化因子在胆道闭锁肝脏中的表达模式并证实 带有这些趋化因子受体的淋巴细胞运输到肝脏。肝 胆道闭锁患者的组织将通过核糖核酸酶进行分析 保护测定和免疫组织化学染色以确定特异性 趋化因子及其细胞来源和 T 细胞亚群 这些趋化因子的受体。具体目标 2 将确定细胞凋亡是否 参与胆道闭锁的胆管闭塞。具体来说，我们 将确定胆道中凋亡细胞的范围和定位 肝闭锁。此外，我们还会检查胆道闭锁肝脏是否有以下情况： 存在明确的细胞凋亡介质并确定其子集 表达这些介质的浸润细胞。在具体目标 3 中，我们将 利用 cDNA 微阵列策略来比较基因表达模式 疾病早期和晚期以及其他阶段的胆道闭锁 胆汁淤积性肝脏病理。这种方法将提供机会 鉴定参与胆汁疾病发病机制的已知和新基因 闭锁。我们预计这些研究将为我们提供独特的见解 胆道闭锁的发病机制并为未来的研究奠定基础 与这种严重而神秘的肝病有关。