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Pathogenic Mechanisms of Virus Induced Biliary Atresia

病毒性胆道闭锁的发病机制

基本信息

批准号：
7261173
负责人：
GREGORY M TIAO
金额：
$ 12.58万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7261173
关键词：
Address Biliary Biliary Atresia Binding Sites Biological Assay CCL2 gene Cell Line Cell surface Cells Cellular Immunity Cessation of life Child Childhood Cholestasis Clinical Coupled Development Disease Epithelial Cells Event Experimental Models Flow Cytometry Future Gene Activation Genes Genome Hepatic Immune response In Vitro Inbred BALB C Mice Infant Infection Inflammatory Inflammatory Response Injury Integrins Ligands Liver Liver diseases Luciferases Macaca mulatta Measures Messenger RNA Mining Modeling Molecular Monoclonal Antibodies Mononuclear Mus NF-kappa B Neonatal Newborn Infant Numbers Operative Surgical Procedures Pathogenesis Pathway interactions Patients Peptides Phenotype Play Predisposition Process Production Promoter Regions Property Proteins RANTES RNA Interference Reporter Research Design Research Personnel Role Rotavirus Rotavirus Infections Sampling Sequence Analysis Signal Transduction Pathway Source Staging Testing Therapeutic Tropism Viral Viral Pathogenesis Virus Virus Diseases Western Blotting base biliary tract chemokine cholangiocyte concept design environmental agent functional genomics gel mobility shift assay genetic element in vitro Model in vivo inhibitor/antagonist insight liver transplantation mouse model novel programs receptor reconstruction transcription factor

项目摘要

DESCRIPTION (provided by applicant): Biliary atresia is the most common cause of neonatal cholestasis and if untreated results in end-stage liver disease (ESLD) and death. Even with current treatment strategies most children develop progressive liver disease and require liver transplantation for salvage. Biliary atresia is the number one indication for pediatric liver transplantation. Despite its importance, the pathogenesis of biliary atresia is unknown. One possible cause is an infection by an environmental agents such as viruses in a susceptible host. We established an experimental mouse model of biliary atresia and found that biliary injury in mice could be induced by a specific rotavirus species - rhesus rotavirus (RRV) in a susceptible murine host - BALB/c mice that progresses to ESLD and death. The inflammatory cholangiopathy is initiated at the biliary epithelial cell level and mirrors the disease process that is found in infants. This model will be used to define the molecular mechanisms regulating the interaction between a virus and the biliary system testing the over-arching hypothesis that the biliary atresia results from the abnormal recognition and infection of biliary epithelial cells (cholangiocytes) by a virus. This hypothesis will be addressed by the following specific aims: 1) Determine the specific RRV gene(s) necessary for the induction of biliary atresia in mice. 2) Determine the mechanism by which the cholangicoyte is susceptible to RRV infection. 3) Determine the mechanism by which RRV infected cholangiocytes triggers a host inflammatory response. The rotavirus property of gene reassortment will be used to identify the RRV gene(s) that cause the murine model of biliary atresia. A novel in vitro model in which RRV is able to infect a cholangiocyte cell line will be used to identify the mechanism by which RRV infects the cholangicoyte. Flow cytometry was used to detect the presence of the integrin apha2beta1 known to confer vulnerabiity to rotavirus infection. Blocking studies using natural ligands and monoclonal antibodies against this protein will be performed to determine its role. In vitro, cholangiocytes infected by RRV produce chemokines. This may be the triggering mechanism by which the host inflammatory response is initiated. We will determine if a similar process occurs in vivo. We will also determine if the NF-kappaB intracellular pathway is the mechansim by which RRV infection induces chemokine production.

描述（由申请人提供）：