IMMUNE-MEDIATED BILE DUCT INJURY IN BILIARY ATRESIA

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， 胆道系统闭塞或中断。这种情况的发生率 新生儿胆汁淤积性疾病是全世界每10，000个活产婴儿中的1个。如果放任 未经治疗的胆道闭锁导致终末期肝病， 出生后8个月的存活率。因此，胆道闭锁是最常见的 小儿肝移植适应症。病因仍然不明 并且关于疾病进展的信息很少。我们所获得 解释特定淋巴细胞亚群定位的初步数据， 胆道闭锁肝此外，我们还确定了 胆管细胞死亡。本研究的目的是阐明 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 表达模式的趋化因子在胆道闭锁肝，并证实， 具有这些趋化因子受体的淋巴细胞运输到肝脏。肝 将通过核糖核酸酶分析来自胆道闭锁患者的组织 保护试验和免疫组织化学染色，以确定特定的 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。如果细胞凋亡被抑制，特异性目标2将建立。 参与胆道闭锁的胆管闭塞。我们特别 将确定胆管中凋亡细胞的程度和定位， 肝闭锁此外，我们还将检查胆道闭锁的肝脏， 存在明确的凋亡介质，并确定 表达这些介质的浸润细胞。在第三阶段，我们将 利用cDNA微阵列策略比较基因表达模式， 胆道闭锁在疾病的早期和晚期以及其他 胆汁淤积性肝病这种方法将提供机会， 确定参与胆道疾病发病机制的已知和新基因， 闭锁我们预计，这些研究将提供独特的见解， 胆道闭锁的发病机制，并为今后的研究奠定基础 与这种严重而神秘的肝病有关。

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.