IMMUNE-MEDIATED BILE DUCT INJURY IN BILIARY ATRESIA

说明(改编自应用程序) 胆道闭锁是一种非常严重的新生儿疾病，其中有一种 胆道系统的破坏或中断。这种情况的发生率 全球新生儿胆汁淤积症的比例为每10,000名活产中就有1名。如果离开 未经治疗的胆道闭锁导致终末期肝病 出生后存活8个月。因此，胆道闭锁是最常见的 小儿肝移植的适应证。病因尚不清楚。 而且关于疾病进展的信息也很少。我们已经获得了 解释特定淋巴细胞亚群定位的初步数据 胆道闭锁，肝脏。此外，我们已经确定了候选调解人 胆管细胞死亡。这项研究的目的是阐明 导致淋巴细胞在肝脏和肝脏中聚集的免疫调节事件 胆管的破坏。在具体目标1中，我们建议设立 趋化因子在胆道闭锁肝组织中的表达 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用核糖核酸酶进行分析 保护性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。特定目标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 将决定胆汁中凋亡细胞的范围和定位 肝脏闭锁。此外，我们还将检查胆道闭锁的肝脏 明确定义的凋亡介体的存在，并确定 表达这些介质的渗透细胞。在具体目标3中，我们将 利用基因芯片技术比较不同性别间基因表达谱 疾病早期和晚期的胆道闭锁以及其他 胆汁淤积性肝脏病理。这一方法将提供以下机会 发现参与胆道疾病发病机制的已知和新基因 闭锁。我们预计，这些研究将为 胆道闭锁的发病机制，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.