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

摘要 这是加州大学肝病学家Jennifer Y.Chen博士申请R03奖， 旧金山(加州大学旧金山分校)。陈医生的长期职业目标是成为一名独立资助的医生 科学家，她投入了75%以上的时间来建立和维护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(HSCs)的激活和灭活HSCs的治疗推动的 具有作为抗纤维化药物的临床应用潜力。陈博士研究计划的总体目标是开发新的 肝纤维化临床治疗中的抗肝纤维化治疗。她已经证明了神经鞘糖脂 神经酰胺通过抑制YAP/TAZ信号通路使HSCs失活。在这项提案中，候选人寻求 阐明神经酰胺如何调节YAP/TAZ途径的上游效应分子以灭活HSCs并减少 肝纤维化。申请人将利用功能获得和功能丧失的方法进行体外培养。 学习。她还将进行免疫共沉淀实验，以确定神经酰胺 调节与关键调节器的相互作用。在活体研究中，她将分析条件基因敲除小鼠 在纤维化的小鼠模型中。一个正式的指导委员会和咨询团队将提供监督， 指导和帮助候选人实现她的目标。研究环境，包括 胃肠病学部和加州大学旧金山分校肝脏中心，将提供丰富的、协作的和支持的 确保候选人成功的氛围。从成功中获得的机械性理解 拟议研究的完成有望揭示合理的疾病修改的新节点和目标 在肝纤维化中，一种治疗选择有限的疾病。研究完成后，将会产生 成功申请R01所需的数据和发布记录，并显著促进过渡 一位独立的内科医生兼科学家。

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.