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Fetal Mechanisms of Liver and Bile Duct Repair: A Link to the Prenatal Origins of Biliary AtresiaBiliary atresia (BA) is the most common indication for liver transplantation in children worldwide. Estimated to occur in ~1:15,000 live births in the US, BA is characterized by periportal inflammation and bile duct obliteration that is thought to be triggered by bile duct epithelial injury. Current therapy relies on early diagnosis and early surgical drainage via a Kasai portoenterostomy. Despite early intervention, most patients develop progressive liver cirrhosis and require a liver transplant. Treatments for BA directed at reducing biliary inflammation have not improved post-Kasai bile drainage or changed the overall survival of patients with their native liver.
Although considerable work has been done to understand the mechanisms of immune-mediated bile duct injury in postnatal mouse models, little is known about the mechanisms of fetal liver and bile duct repair that when perturbed, may predispose patients to developing BA. Our lab is focused on understanding the mechanisms by which the fetus may repair liver and bile duct injury. This line of research will lead to discoveries and testable therapeutics that can be used in the postnatal setting to revert neonatal inflammation to a more “fetal” and reparative state in patients with BA. Defining the Spatial and Temporal Relationships Between Tissue Resident Macrophages and Developing Hepatocytes and CholangiocytesUsing genetic tools in mice, we are able to label tissue resident macrophages (TRMs) in the fetal liver. We are characterizing where and when TRMs localize in relation to the development of hepatocytes and cholangiocytes. Generating a Cell Atlas of the Developing LiverIn collaboration with Dr. Bruce Wang and the Wang Lab, we have utilized single cell technology to create a transcriptome of the developing fetal liver. We will use this atlas to identify novel immune populations in the developing liver. This will lead to further investigations regarding the role of these immune cell populations in the development of the fetal liver. |