权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Genetic basis of virus induced Biliary Atresia

病毒引起的胆道闭锁的遗传基础

基本信息

批准号：
10328541
负责人：
GREGORY M TIAO
金额：
$ 44.58万
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：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328541
关键词：
Activated Natural Killer Cell Adoptive Transfer Amino Acids Anti-Inflammatory Agents Antiviral Response Arginine Attenuated Award Biliary Biliary Atresia Binding Binding Proteins Cells Child Childhood Cholestasis Coculture Techniques Cytokine Signaling Data Dendritic Cells Development Disease Drainage procedure Endocytosis Endosomes Epithelial Epithelial Cells Etiology Extrahepatic Extrahepatic Cholestasis Genes Genetic Glycine Glycyrrhizic Acid Goals HMGB1 Protein Hsc70 protein Icterus Immune mediated destruction Immune response Immune system In Vitro Infant Infection Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Innate Immune System Interferon Type I Label Liver Mediating Mediator of activation protein Membrane Molecular Molecular Profiling Mus Mutate Mutation NK Cell Activation Natural Killer Cells Newborn Infant Obstruction Operative Surgical Procedures Pathogenesis Pathologic Pathway interactions Patients Pattern Perinatal Phenotype Play Population Positioning Attribute Proteins Rhesus Role Rotavirus Rotavirus Infections Sampling Signal Pathway Signaling Molecule Site Symptoms System TLR3 gene Testing Therapeutic Agents Viral Viral Pathogenesis Virus Virus Diseases biliary tract chemokine cholangiocyte cytokine differential expression end stage liver disease epithelial injury extracellular imaging study immune activation in vivo infancy insight live cell imaging liver transplantation mortality mouse model mutant neonatal mice novel novel therapeutics p38 Mitogen Activated Protein Kinase pathogen pathogenic virus receptor receptor binding reconstruction recruit response reverse genetics trafficking treatment strategy

项目摘要

Project Summary/Abstract Biliary atresia is the most common cause of pediatric end stage liver disease and the number one indication for pediatric liver transplantation. Because pathogenic viruses have been found in the liver of afflicted children, a proposed etiology for biliary atresia is a perinatal viral infection triggering immune mediated destruction of the biliary epithelium. The murine model of biliary atresia supports a viral pathogenesis as newborn mice infected with rhesus rotavirus (RRV) develop inflammation within the portal tract and extrahepatic bile duct obstruction. RRV targets the cholangiocyte for infection and in addition to direct cholangiocyte injury also induces Natural Killer cell mediated injury to the biliary epithelium. We have previously shown that the amino acid, arginine (R) within the sequence “SRL” (amino acids 445-447) on the RRV VP4 protein is required for viral binding and entry into biliary epithelial cells. We developed a reverse genetics system to create a mutant of RRV (RRVVP4-R446G), which had a single amino acid change in VP4 protein compared to wild type RRV. In vitro, the mutant virus had reduced binding and infectivity in cholangiocytes. In vivo, it produced less symptoms and mortality in neonatal mice, resulting in an attenuated form of biliary atresia. We will use this mutant strain along with additional VP4 mutants to determine how RRV binds to, enters, traffics through the cell, and ultimately activates the cholangiocyte's innate immune response. We will also ascertain these VP4 mutants' ability to infect and activate plasmacytoid dendritic cells leading to Natural Killer cell activation. These complimentary approaches will generate new insight in viral induced biliary atresia.

项目总结/摘要胆道闭锁是小儿终末期肝病最常见的原因，小儿肝移植的一个适应症。因为致病病毒已经在胆道闭锁的病因是围产期病毒感染引发免疫介导的胆管上皮破坏。胆管炎小鼠模型新生小鼠感染恒河猴轮状病毒（RRV）后，门脉道内出现炎症和肝外胆管阻塞。RRV目标胆管细胞的感染，除了直接的胆管细胞损伤也诱导自然杀伤细胞介导的胆管上皮损伤。我们先前已经表明，序列“SRL”（氨基）内的氨基酸精氨酸（R）氨基酸445-447）是病毒结合和进入胆管上皮细胞所必需的细胞我们开发了反向遗传学系统来创建RRV的突变体（RRVVP 4-R446 G），与野生型RRV相比，在VP 4蛋白中具有单个氨基酸变化。在体外，突变体病毒在胆管细胞中的结合和感染性降低。在体内，和新生小鼠的死亡率，导致胆道闭锁的减弱形式。我们将使用这个突变株沿着额外的VP 4突变体，以确定RRV如何结合、进入、运输并最终激活胆管细胞的先天免疫反应。我们将还确定了这些VP 4突变体感染和激活浆细胞样树突状细胞的能力，自然杀伤细胞激活这些互补的方法将产生新的见解，诱发胆道闭锁。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rotavirus replication in the cholangiocyte mediates the temporal dependence of murine biliary atresia.

DOI：
10.1371/journal.pone.0069069
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Mohanty SK;Donnelly B;Bondoc A;Jafri M;Walther A;Coots A;McNeal M;Witte D;Tiao GM
通讯作者：
Tiao GM

Role of myeloid differentiation factor 88 in Rhesus rotavirus-induced biliary atresia.

骨髓分化因子 88 在恒河猴轮状病毒诱导的胆道闭锁中的作用。

DOI：
10.1016/j.jss.2013.05.032
发表时间：
2013
期刊：
The Journal of surgical research
影响因子：
0
作者：
Walther,AshleyE;Mohanty,SujitK;Donnelly,Bryan;Coots,Abigail;McNeal,Monica;Tiao,GregoryM
通讯作者：
Tiao,GregoryM

Rotavirus infection of human cholangiocytes parallels the murine model of biliary atresia.