Chronic liver disease is a common cause of morbidity in the U.S.A. with around 5.5 million Americans suffering from hepatic fibrosis and cirrhosis. Chronic liver injury can be the result of any number of insults alone or in combination, including alcohol, viral hepatitis, metabolic defect or others. Cirrhosis can be further complicated by liver failure, portal hypertension and development of hepatocellular cancer (HCC), making chronic liver disease as the 12th leading cause of mortality in the U.S.A and a major socio-economic burden. The NIH action plan for liver research, identifies areas such as understanding cellular and molecular processes of normal liver cell functioning;liver regeneration and development;and hepatic fibrosis;to make an overall impact on liver health. The present grant is focused on understanding the role of a lesser known molecule in hepatocyte biology, platelet derived growth factor receptor-alpha (PDGFR?) based on some intriguing observations made over last several years. High expression and phosphorylation of PDGFR? was identified during early stages of liver development in mice. Specifically, hepatoblasts and immature hepatocytes displayed high expression at early hepatic developmental stages that coincide with ongoing cell proliferation and cell survival. Blocking PDGFR? in embryonic liver culture verified these effects thus warranting an in depth investigation. Similarly, we have identified a dramatic increase in PDGFR? temporally during liver regeneration after two-third or partial hepatectomy (PH) in mice. Lastly, PDGFR? upregulation was observed in hepatocytes during hepatic fibrosis in patients, and after bile duct ligation (BDL) in mice. In order to unequivocally address the role of PDGFR? in liver growth &development, we have generated several mouse models that will enable us to address the overarching hypothesis that 'PDGFR? is a critical mediator of hepatocyte proliferation and survival and aberrations in its regulation lead to significant disruption of liver homeostasis leading to disorders of hepatic growth including aberrant development, regeneration, fibrosis &cirrhosis'. We propose to investigate this hypothesis through three specific aims, which are distinct and employ balanced in vivo and in vitro approaches.
In aim 1, we propose to investigate PDGFR? signaling in early liver development via comprehensive ontogenic analysis to address its role and regulation. These studies will be complemented by generation of conditional null mice that lack PDGFR? in hepatoblasts.
In aim 2, we will study PDGFR? signaling during liver regeneration in partial hepatectomy model and then address the impact of PDGFR? overexpression and deletion in hepatocytes on regenerative response utilizing novel animal models generated in the lab.
In aim 3, we will study PDGFR? signaling in hepatic fibrosis and cirrhosis in murine models of bile duct ligation and carbon tetrachloride administration. These studies will be complemented by examining the cellular and molecular basis of the disease process in absence or overexpression of PDGFR? in hepatocytes in novel transgenic mice in our lab and complemented by utilization of species-specific PDGFR? blocking antibodies to determine impact on disease progression in these models to address therapeutic efficacy. Thus, this highly significant proposal will unequivocally and comprehensively address the role and regulation of PDGFR? in liver health and disease.
The project comprehensively investigates the role of Platelet derived growth factor receptor-alpha (PDGFR?) and its downstream signaling in liver development, regeneration, fibrosis and cancer. This will allow modulation of this signaling mechanism in various hepatic pathologies since such PDGFR? inhibitors are currently available for therapies in patients.
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