Biliary atresia is the most common cause of chronic cholestasis in children and the leading indication for pediatric liver transplantation worldwide. The disease is multifactorial and results from an inflammatory and fibrosing obstruction of the bile ducts that begins within the first two months of life. Using functional genomics to search for underlying pathogenic mechanisms of disease, we found a unique transcriptional program in affected livers, with a coordinate activation of genes regulating lymphocyte differentiation. Based on these data, we hypothesize that biliary atresia results from an immune-mediated destruction of the biliary cells. We will address this hypothesis in three related specific aims using complimentary human- and animal-based approaches.
In Aim 1 : """"""""To establish the functional polarization of lymphocytes during disease progression"""""""", we will quantify the expression of TH1 and TH2 cytokines in the liver, the phenotype of circulating T lymphocytes, and the activation of dendritic (antigen-presenting) cells in children with biliary atresia at different stages of disease.
In Aim 2 : """"""""To identify the cellular effectors and molecular pathways of inflammatory injury to bile ducts"""""""", we will use a novel model of rotavirus-induced inflammation and obstruction of bile ducts in neonatal mice recently established in our laboratory. In these mice, we will define the cellular target of rotavirus in the biliary system in vivo and in a cell culture system, and determine the temporo-spatial regulation of virus-induced inflammation of the bile ducts. We will also establish the functional differentiation of hepatic lymphocytes to a proinflammatory phenotype within the biliary system in response to viral infection, and dissect the coexisting inflammatory pathways that work in synergism with T cells to induce biliary injury. And through mechanistic studies in Aim 3: """"""""To directly establish the regulatory role of T cells in biliary injury after neonatal viral infection"""""""", we will determine whether the wholesale loss of T and/or B lymphocytes renders bile ducts resistant to rotavirus-induced injury. Then, we will explore the key role of specific molecular mechanisms used by lymphocytes to target the bile ducts via viral challenge of mice genetically engineered to lack or overproduce a TH1 response. Together, the combined (human and mouse) approaches will provide novel insight into mechanisms of biliary injury, and uncover molecular targets for potential therapeutic strategies to inhibit disease progression in children with biliary atresia.
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