ROLE OF RHESUS ROTAVIRUS GENE 4 IN BILIARY ATRESIA

恒河猴轮状病毒基因 4 在胆道闭锁中的作用

基本信息

批准号：
8358153
负责人：
KAROL SESTAK
金额：
$ 3.72万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8358153
关键词：
Affect Attenuated Biliary Biliary Atresia Binding Biological Assay Childhood Disease Double Stranded RNA Virus Epithelial Cells Etiology Funding Genes Grant In Vitro Infection Macaca mulatta Modeling Mus NR4A1 gene National Center for Research Resources Obstruction Pathogenesis Perinatal Infection Phenotype Play Primates Principal Investigator Property Proteins Research Research Infrastructure Resources Role Rotavirus Source Translating Tropism United States National Institutes of Health Viral base cholangiocyte cost gain of function in vivo loss of function mortality

Affect Attenuated Biliary Biliary Atresia Binding Biological Assay Childhood Disease Double Stranded RNA Virus Epithelial Cells Etiology Funding Genes Grant In Vitro Infection Macaca mulatta Modeling Mus NR4A1 gene National Center for Research Resources Obstruction Pathogenesis Perinatal Infection Phenotype Play Primates Principal Investigator Property Proteins Research Research Infrastructure Resources Role Rotavirus Source Translating Tropism United States National Institutes of Health Viral base cholangiocyte cost gain of function in vivo loss of function mortality

展开

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Biliary atresia (BA) is a devastating disease of childhood. The etiology of BA remains uncertain; however, increasing evidence supports a viral component in disease pathogenesis. The murine model of BA is induced by perinatal infection with rhesus rotavirus (RRV) but not by other strains of rotavirus an example of which is TUCH. Rotavirus is a double-stranded RNA virus that contains 11 gene segments. To determine which RRV gene segment is responsible for disease pathogenesis, we used the parental strains RRV and TUCH and the rotavirus property of reassortment to generate a complete set of single gene reassortants. Eleven single-gene "loss-of-function" reassortants in which a TUCH gene replaced its RRV equivalent and eleven reciprocal single gene "gain-of-function" reassortants in which a RRV gene replaced its TUCH equivalent were generated. Infection of mice with the "loss-of-function" reassortant RT4 where gene segment 4 from TUCH was placed on an RRV background eliminated RRV's ability to cause murine BA. In a reciprocal fashion, the "gain-of-function" reassortant TR4 resulted in murine BA with a mortality rate of 95%. Cholangiocyte binding and infectivity assays revealed RT4 binding ratio and titer (both in vivo and in vitro) were significantly attenuated as compared with RRV; moreover, TR4 binding and titer were significantly higher than TUCH. Reassortant RT3 and TR3 induced an intermediate phenotype. Gene segment 4 through its translated gene product VP4 plays a significant role governing RRV tropism for the biliary epithelial cell and induces the murine model of biliary atresia. The basis for tropism and how it induces biliary obstruction requires further study. Substitution of RRV gene segment 3 did not affect viral infectivity in vitro, but altered the in vivo effect.

该副本是利用资源的众多研究子项目之一由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持而且，副投影的主要研究员可能是其他来源提供的包括其他NIH来源。列出的总费用可能代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。胆道闭锁（BA）是一种破坏性的童年疾病。 BA的病因仍然不确定。但是，越来越多的证据支持疾病发病机理中的病毒成分。 Ba的鼠模型是由围绕轮状病毒（RRV）的围产期感染诱导的，但没有其他轮状病毒菌株是一个例子。轮状病毒是一种双链RNA病毒，包含11个基因段。为了确定哪个RRV基因段负责疾病发病机理，我们使用了父母菌株RRV和TUCH以及REASORSTREMT的轮状病毒特性来产生一组完整的单基因重构体。 11个单基因“功能丧失”可归结药物，其中Tuch基因取代了其RRV等效物和11个相互的单基因“功能获得”的real-分类者，其中RRV基因替换了其TUCH等效物。将“功能丧失”的REASORTANT RT4的小鼠感染，其中将TUCH的基因段4放置在RRV背景上，从而消除了RRV引起Murine Ba的能力。以相互的方式，“功能奖励”可重新成分TR4导致鼠ba死亡率为95％。与RRV相比，胆管细胞结合和感染性测定显示RT4结合比和滴度（体内和体外）都显着减弱。此外，TR4结合和滴度明显高于TUCH。 Reastrant RT3和TR3诱导了中间表型。基因段4通过其翻译的基因产物VP4在胆汁上皮细胞的RRV tropism中起重要作用，并诱导了胆道闭锁的鼠模型。向往往的基础及其如何诱导胆道阻塞需要进一步研究。 RRV基因段3的替代不会影响体外病毒感染性，而是改变了体内效应。