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）中起病因作用，BA是婴儿期最严重的消化/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，并且方法学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）的组织库提供了系统搜索这种疾病的长期怀疑的病毒病因的机会，并且该BARC辅助研究提出应用一种强大的和新颖的病毒发现方法，使用DNA微阵列，该微阵列包含来自GenBank中每个完全测序的病毒基因组的最高度保守的70聚体寡核苷酸序列。病毒基因组保守区域的战略靶向不仅能够对基本上所有已知病毒进行大规模平行分析，而且还可以最大限度地提高检测未知病毒的概率。病毒病因的鉴定应作为重点研究疾病机制、治疗和预防的起点。 该建议旨在将这种强大的新方法应用于BA的可能病毒病因学的调查，通过检查在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物。将检查来自“胚胎”表型患者的少量组织，以及来自已知非病毒性肝病（如α-1-抗胰蛋白酶缺乏症、阿拉吉耶综合征等）患者的少量组织作为对照组织。王博士在华盛顿大学圣刘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爆发期间，使用泛病毒微阵列观察到的杂交模式有助于将SARS鉴定为一种新型冠状病毒，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.