Chronic liver disease encompasses the steady destruction of hepatic tissue over time, resulting in the replacement of healthy liver tissue with damaged fibrotic and cirrhotic tissue. Among other symptoms, cirrhosis manifests itself with regenerative hepatic nodules and portal hypertension, triggering a loss of liver functionality and poor quality of life. Moreover, in the United States, cirrhosis remains the 12th leading cause of death, incurring healthcare costs of billions of dollars in the process. Despite these astronomical costs and limited palliative care, the only effective treatment for cirrhosis is liver transplantaton. The demand for liver transplants however, far exceeds the availability of donor livers, underpinning the need for harnessing the liver's innate regenerative capacity. With that regard, we aim to understand the complete process of biliary epithelial cell (BEC)-driven liver regeneration: when hepatocyte proliferation is compromised following severe liver injury, BECs proliferate and contribute to the regenerating hepatocytes. Our lab has previously characterized the zebrafish model of BEC-driven liver regeneration, in which the BECs de-differentiate into hepatoblast-like cells (HB-LCs), proliferate and then re-differentiate into hepatocytes. Specifically, during this regenerative process, we found upregulation of the inhibitor of differentiation protein, Id2a. Using zebrafish as a model organism, the purpose of this proposal is to elucidate the role of Id2a in BEC-driven liver regeneration and liver development, since events involved in liver regeneration can also be implicated in liver development. We will utilize both loss- and gain-of-function approaches, including knockdown via antisense morpholino oligos (MOs), id2a mutants and an id2a overexpression heat-shock inducible line, Tg(hsp70: mCherry-T2A-id2a). These tools along with previously generated reagents in our lab will be instrumental in exposing the process by which the liver develops, sustains injury and subsequently regenerates to restore lost liver mass. Understanding these distinctive yet connected mechanisms will provide us with new insights to improve innate liver regeneration and develop novel therapies to treat chronic liver diseases.

Public Health Relevance

Chronic liver disease and cirrhosis are the 12th leading cause of death in the United States. Unfortunately, the only effective therapy for chronic liver diseases is liver transplantation, which is inadequate due to a shortage of donor livers. By identifying the important mediators and molecular candidates of liver regeneration and liver development, we can augment the innate regenerative process to increase survival and reduce disease severity. Hence, the goal and studies defined in this proposal aim to elucidate the underlying mechanisms of BEC-driven liver regeneration and liver development by assessing the role of inhibitor of differentiation protein, Id2a, in these processes. Completion of the outlined work wil offer valuable insights and establish novel therapies to enhance innate liver regeneration.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDK1-GRB-2 (J1))
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Densmore, Christine L
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University of Pittsburgh
Anatomy/Cell Biology
Schools of Medicine
United States
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So, Juhoon; Khaliq, Mehwish; Evason, Kimberley et al. (2017) Wnt/?-catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating Notch activity. Hepatology :
Choi, Tae-Young; Khaliq, Mehwish; Tsurusaki, Shinya et al. (2017) Bone morphogenetic protein signaling governs biliary-driven liver regeneration in zebrafish through tbx2b and id2a. Hepatology 66:1616-1630
Khaliq, Mehwish; Choi, Tae-Young; So, Juhoon et al. (2015) Id2a is required for hepatic outgrowth during liver development in zebrafish. Mech Dev 138 Pt 3:399-414
Choi, Tae-Young; Khaliq, Mehwish; Ko, Sungjin et al. (2015) Hepatocyte-specific ablation in zebrafish to study biliary-driven liver regeneration. J Vis Exp :e52785