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

肝纤维形成中的神经酰胺、AMPK 和 YAP/TAZ 信号转导

• 批准号: 10544748
• 负责人: Jennifer Y. Chen
• 金额: $ 12.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544748
• 关键词: 5' -AMP-activated protein kinase; Advisory Committees; Award; Basic Science; Biochemical; California; Carbon Tetrachloride; Ceramides; Clinical; Clinical Treatment; Co-Immunoprecipitations; Data; Development; Disease; Disease Progression; Ensure; Environment; Enzyme Inhibition; Fibrosis; Funding; Gastroenterology; Goals; Hepatic Fibrogenesis; Hepatic Stellate Cell; Human; Hydrolysis; In Vitro; Knockout Mice; Knowledge; LATS1 gene; Life; Liver; Liver Failure; Liver Fibrosis; Mediating; Mentorship; Mission; Modeling; Modification; Molecular; Molecular Biology; Mus; Outcome; Pathway interactions; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Physicians; Public Health; Publications; Regulation; Research; Role; San Francisco; Scientist; Signal Pathway; Signal Transduction; Sphingolipids; Supervision; Techniques; Therapeutic; Time; United States National Institutes of Health; Universities; Work; antifibrotic treatment; candidate identification; career; cell type; chronic liver disease; collaborative environment; conditional knockout; druggable target; experimental study; fibrogenesis; gain of function; galactosylgalactosylglucosylceramidase; improved; in vivo; loss of function; mouse model; non-alcoholic fatty liver disease; novel; novel therapeutics; preclinical development; programs; success; supportive environment

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.

抽象的 这是加州大学肝病学家 Jennifer Y. Chen 博士提交的 R03 奖申请， 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师 科学家，投入超过 75% 的时间来建立和维护基础科学研究项目 肝纤维化。纤维化是由肝星状细胞 (HSC) 的激活和 HSC 灭活疗法驱动的 具有作为抗纤维化药物的临床潜力。陈博士研究计划的总体目标是开发新颖的 抗纤维化疗法用于临床治疗肝纤维化。她证明了鞘脂 神经酰胺通过抑制 YAP/TAZ 信号通路来灭活 HSC。在此提案中，候选人寻求 阐明神经酰胺如何调节 YAP/TAZ 通路的上游效应器以灭活 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 研究。她还将进行免疫共沉淀实验，以确定神经酰胺的程度 调节与主要监管机构的互动。对于体内研究，她将分析条件基因敲除小鼠 在纤维化小鼠模型中。正式的导师委员会和顾问团队将提供监督， 为候选人实现其目标提供指导和帮助。研究环境，包括 胃肠病学部门和 UCSF 肝脏中心将提供丰富的、协作的和支持性的 确保候选人成功的氛围。从成功的案例中获得的机械理解 拟议研究的完成有望揭示合理疾病调整的新节点和目标 肝纤维化是一种治疗选择有限的疾病。完成研究将产生 成功 R01 申请所需的数据和发布记录，并显着促进过渡 独立医师科学家的候选人。