STRATEGIC TARGETING OF VIRAL GENOMES IN BILIARY ATRESIA

描述(由申请人提供)：我们假设病毒感染可能在胆道闭锁(BA)中起病因学作用，BA是婴儿最严重的消化/肝脏疾病之一。然而，到目前为止，分离或发现BA患者中的病毒的尝试仅限于少数患者，产生了相互矛盾的结果，而且方法仅限于寻找已知病毒的血清学和/或组织分析。胆道闭锁研究联盟(BARC)的组织储存库提供了系统搜索这种疾病的长期怀疑的病毒病原学的机会，BARC的这项辅助研究建议应用一种强大而新颖的病毒发现方法，使用包含GenBank中每个完全测序的病毒基因组中最保守的70聚体寡核苷酸序列的DNA微阵列。以病毒基因组保守区域为战略目标，不仅能够大规模并行分析基本上所有已知的病毒，而且还最大限度地增加了检测未知病毒的可能性。病毒病原学的确定应作为进一步研究疾病机制、治疗和预防的起点。 这项建议旨在将这一强大而新颖的方法应用于BA可能的病毒病因学的研究，方法是检查BARC中具有“获得性”或“围产期”表型的EHBA患者的肝脏和胆管残留。一小部分组织将从‘胚胎’表型患者和已知的非病毒性肝病患者(如α-1抗胰蛋白酶缺乏症、Alagille综合征等)作为对照组织进行检查。王博士在华盛顿大学圣路易斯的实验室一直处于新病毒发现的前沿。例如，在最近的SARS疫情期间，使用泛病毒微阵列观察到的杂交模式有助于将SARS确定为一种新的冠状病毒，证明了这种方法的力量和实用性。

DESCRIPTION (provided by applicant): We hypothesise that viral infection could play an etiologic role in biliary atresia (BA), one of the most serious digestive/liver diseases of infancy. However, to date attempts to isolate or discover viruses in patients with BA have been limited to small numbers of patients, have yielded conflicting results, and the methodology has been limited to serological, and/or tissue analysis looking for known viruses. The Biliary Atresia Research Consortium's (BARC) tissue repository offers the opportunity for systematic search for the long-suspected viral etiology of this disease and this BARC Ancillary Study proposes to apply a powerful and novel method of viral discovery, using a DNA microarray harboring the most highly conserved 70mer oligonucleotide sequences from every fully sequenced viral genome in GenBank. Strategic targeting of the conserved regions of viral genomes enables not only massively parallel analysis of essentially all known viruses, but also maximizes the probability of detecting unknown viruses. Identification of a viral etiology should serve as the launching point for additional studies focused on disease mechanisms, treatment and prevention. This proposal aims to apply this powerful and novel methodology to the investigation of a possible viral etiology of BA, by examining liver and bile duct remnants from EHBA patientsenrolled in the BARC with the `acquired' or `perinatal' phenotype. A small number of tissues will be examined from patients with the `embryonal' phenotype, and from patients with known non-viral liver diseases eg alpha-1-antitrypsin deficiency, allagille syndrome etc. as control tissue. Dr Wang's laboratory at Washington University St Louis has been at the forefront of new viral discovery. For example, during the recent SARS outbreak, hybridization patterns observed using the pan-viral microarray helped identify SARS as a novel coronavirus, demonstrating the power and utility of this approach.