Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism

肝脂肪酶、PPAR-δ 和脂肪酸代谢

• 批准号: 9275086
• 负责人: JONATHAN David BROWN
• 金额: $ 0.93万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275086
• 关键词: Hepatic; Lipase; PPAR; delta; Fatty

Project Summary/Abstract This NIH Mentored Clinical Scientist Research Career Development Award proposal describes a five-year training program for career development in academic cardiovascular medicine. The principle investigator has completed clinical fellowship in Cardiovascular Medicine at Brigham and Women's Hospital and will embark on a research program designed to train for an independent career in disease-oriented research. The principal investigator will acquire in-depth experience in transcription, cell biology, metabolism, lipid chemistry, and analytical approaches to chemistry including mass spectrometry as well as integrated physiologic studies in vivo. Both Dr. Jorge Plutzky and Dr. Alan Saghatelian will mentor the principal investigator's scientific development during this period. Dr. Plutzky is a scientific leader in transcriptional regulation of lipid metabolism and vascular inflammation with an established track record. Dr. Plutzky has mentored other trainees to successful careers in biomedical investigation. Dr. Saghatelian is an established leader in the field of lipid metabolomics and lipid chemistry in the Department of Chemistry, Harvard University. At the interface between chemistry and biology, this career development award creates a unique training environment for the applicant. This comprehensive program described will be further enhanced by collaborations in the research quadrangle and Department of Chemistry. As the primary location for the project, Harvard Medical School/Brigham and Women's Hospital Center for Excellence in Vascular Biology is an exceptional institutional environment providing innumerable resources to assure the principal investigator's success toward an independent career in academic medicine. We provide novel evidence that hepatic lipase selectively activates peroxisome proliferator-activated receptor-� (PPAR�) transcription in vitro and in vivo through VLDL hydrolysis by generating fatty acid metabolites. This data frames the central hypothesis of this proposal: hepatic lipase selectively activates PPAR� -dependent transcription that coordinates fatty acid metabolism in the liver. We propose to study the mechanisms and the transcriptional and metabolic consequences of hepatic lipase-mediated PPAR� activation in vitro and in vivo. The specific aims are: (1) to study the molecular basis of hepatic lipase- mediated PPAR� activation in vitro; (2) to determine the role of hepatic lipase-mediated PPAR� activation in transcriptional and functional regulation of hepatocyte fatty acid metabolism. These studies will utilize hepatic lipase gain- and loss-of-function techniques and hepatocyte-specific PPAR� deficient mice. An understanding of endogenous PPAR� activation through hepatic lipase action has fundamental implications for the pathogenesis of diseases rooted in metabolic dysfunction including diabetes mellitus and atherosclerosis.

项目摘要/摘要 这份由NIH指导的临床科学家研究职业发展奖提案描述了一个为期五年的 学术心血管医学职业发展培训计划。首席调查员已经 在布里格姆妇女医院完成心血管医学临床研究，并将开始 一项旨在为面向疾病的研究领域的独立职业生涯进行培训的研究计划。校长 研究人员将在转录、细胞生物学、新陈代谢、脂肪化学和 化学分析方法，包括质谱学和综合生理学研究 活着。豪尔赫·普卢茨基博士和艾伦·萨加特利安博士都将指导首席研究员的科学 这一时期的发展。普卢茨基博士是脂类转录调控的科学领袖。 新陈代谢和血管炎症，有既定的记录。普鲁茨基博士曾指导过其他人 受训人员将在生物医学研究领域取得成功。萨格哈特利安博士是该领域公认的领导者。 哈佛大学化学系脂类代谢组学和脂类化学教授。在界面上 在化学和生物之间，这个职业发展奖为学生创造了一个独特的培训环境 申请人。所描述的这一综合计划将通过研究中的合作得到进一步加强 四合院和化学系。作为该项目的主要地点，哈佛医学院 学校/布里格姆妇女医院血管生物学卓越中心是一个特殊的机构 提供无数资源的环境，以确保首席调查员成功地 独立从事学术医学工作。 我们提供了新的证据，证明肝脂酶选择性地激活了由过氧化物体增殖物激活的 受体-�(�)在体内和体外的转录：极低密度脂蛋白通过产生脂肪酸进行水解 代谢物。这些数据框定了这一提议的中心假设：肝脂酶选择性地激活 PPAR依赖于�的转录，协调肝脏中的脂肪酸代谢。我们建议研究 肝脂酶介导的PPAR�的作用机制及其转录和代谢效应 体外激活和体内激活。其具体目的是：(1)研究肝脂酶的分子基础。 (2)探讨肝脂酶介导的PPAR�激活在肝细胞癌中的作用。 肝细胞脂肪酸代谢的转录和功能调节。这些研究将利用肝脏 脂肪酶获得和功能丧失技术和肝细胞特异性PPAR�缺陷小鼠。一种理解 通过肝脂酶作用内源性PPAR�激活的研究具有基础意义 源于代谢功能障碍的疾病的发病机制，包括糖尿病和动脉粥样硬化。