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

摘要 这是Jennifer Y博士的R 03奖申请书。加州大学的肝病学家陈， 旧金山弗朗西斯科（UCSF）。陈博士的长期职业目标是成为一名独立资助的医师 科学家，投入超过75%的时间来建立和维持一个基础科学研究计划， 肝纤维化肝纤维化是由肝星状细胞（HSC）的激活和治疗来驱动的 具有作为抗纤维化剂的临床潜力。陈博士的研究计划的总体目标是开发新的 用于肝纤维化临床治疗的抗纤维化疗法。她证明了鞘脂 神经酰胺通过抑制雅普/TAZ信号通路使HSC失活。在这份提案中，候选人寻求 阐明神经酰胺如何调节雅普/TAZ途径的上游效应子以灭活HSC并减少 肝纤维化申请人将利用功能获得和功能丧失方法进行体外试验。 问题研究她还将进行免疫共沉淀实验，以确定神经酰胺 调节与关键监管机构的互动。对于体内研究，她将分析条件性基因敲除小鼠， 在小鼠纤维化模型中。一个正式的指导委员会和咨询小组将提供监督， 指导和帮助候选人实现其目标。研究环境，其中包括 消化科和加州大学旧金山分校肝脏中心，将提供丰富的，协作和支持 确保候选人的成功。要从成功的 完成拟议的研究有望揭示新的节点和目标，为合理的疾病修改 肝纤维化是一种治疗选择有限的疾病。研究完成后， 成功申请R 01所需的数据和出版物记录，并大大促进了过渡 一个独立的物理学家和科学家。

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.