Ceramide, AMPK, and YAP/TAZ Signaling in Hepatic Fibrogenesis

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ABSTRACT This is an application for an R03 Award by Dr. Jennifer Y. Chen, a hepatologist at the University of California, San Francisco (UCSF). Dr. Chen's long-term career goal is to become an independently funded physician scientist, devoting more than 75% of her time to establish and maintain a basic science research program in hepatic fibrosis. Fibrosis is driven by activation of hepatic stellate cells (HSCs) and therapies to inactivate HSCs have clinical potential as antifibrotic agents. The overall goal of Dr. Chen's research program is to develop novel antifibrotic therapies for the clinical treatment of hepatic fibrosis. She has demonstrated that the sphingolipid ceramide inactivates HSCs by inhibiting the YAP/TAZ signaling pathway. In this proposal, the candidate seeks to elucidate how ceramide regulates upstream effectors of the YAP/TAZ pathway to inactivate HSCs and reduce hepatic fibrogenesis. The applicant will utilize gain of function and loss of function approaches for the in vitro studies. She will also perform co-immunoprecipitation experiments to determine the extent by which ceramide modulates interactions with key regulators. For the in vivo studies, she will analyze conditional knockout mice in a mouse model of fibrosis. A formal mentorship committee and advisory team will provide supervision, guidance, and assistance for the candidate to achieve her goals. The research environment, which includes the Division of Gastroenterology and the UCSF Liver Center, will provide a rich, collaborative, and supportive atmosphere to ensure the candidate's success. The mechanistic understanding to be gained from the successful completion of the proposed studies promises to reveal new nodes and targets for rational disease modification in hepatic fibrosis, a disease with limited treatment options available. Completion of the studies will produce the data and publication record necessary for a successful R01 application and significantly facilitate the transition of the candidate to an independent physician-scientist.