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汁闭锁（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，迄今为止，在BA患者中分离或发现病毒的尝试仅限于少数患者，产生了相互矛盾的结果，并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）的组织库为系统搜索这种疾病的长期怀疑的病毒病因提供了机会，BARC辅助研究建议应用一种强大而新颖的病毒发现方法，使用DNA微阵列，其中包含GenBank中每个完全测序的病毒基因组中最高度保守的70个寡核苷酸序列。对病毒基因组保守区域的战略性定位不仅可以对基本上所有已知病毒进行大规模并行分析，而且可以最大限度地提高检测未知病毒的概率。确定一种病毒的病因应作为进一步研究疾病机制、治疗和预防的出发点。

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.