Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism

肝脂肪酶、PPAR-δ 和脂肪酸代谢

• 批准号: 8197786
• 负责人: JONATHAN David BROWN
• 金额: $ 13.57万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197786
• 关键词: Adenoviruses; Affect; Agonist; Atherosclerosis; Binding; Biology; Blood Vessels; Cardiovascular system; Cell Nucleus; Cells; Cellular biology; Cessation of life; Chemistry; Clinical; Collaborations; Data; Development; Diabetes Mellitus; Disease; Environment; Epidemic; FABP5 gene; Family member; Fatty Acids; Fellowship; Functional disorder; Gene Expression; Genetic Transcription; Goals; Heart Diseases; Hepatic; Hepatocyte; High Density Lipoproteins; Hospitals; Human; Hydrolysis; In Vitro; Individual; Inflammation; Investigation; K-Series Research Career Programs; Ligands; Lipase; Lipid Chemistry; Lipids; Lipolysis; Lipoproteins; Liver; Location; Mass Spectrum Analysis; Mediating; Medicine; Mentors; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Monounsaturated Fatty Acids; Mus; Nuclear Receptors; Obesity; Oleic Acids; PPAR Pathway; PPAR delta; Pathogenesis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Physiological; Plant Roots; Play; Principal Investigator; Production; Protein Family; Public Health; Receptor Activation; Regulation; Research; Research Personnel; Resources; Role; Scientist; Small Interfering RNA; Techniques; Training; Training Programs; Transcriptional Regulation; Uncertainty; United States National Institutes of Health; Universities; Very low density lipoprotein; Western World; Woman; Work; abstracting; activating transcription factor; base; career; career development; design; experience; fatty acid metabolism; hepatic lipase; hepatoma cell; human FABP5 protein; improved; in vivo; insight; insulin sensitivity; lipid metabolism; lipoprotein lipase; liquid chromatography mass spectrometry; loss of function; medical schools; metabolomics; mouse model; novel; overexpression; oxidation; palmitoleic acid; programs; response; success; vascular inflammation

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.

项目概要/摘要 这份 NIH 指导临床科学家研究职业发展奖提案描述了一个五年计划 学术心血管医学职业发展培训计划。主要研究者有 在布莱根妇女医院完成了心血管医学临床研究，并将开始 旨在培训以疾病为导向的研究的独立职业的研究计划。校长 研究人员将获得转录、细胞生物学、新陈代谢、脂质化学和 化学分析方法，包括质谱分析以及综合生理学研究 体内。 Jorge Plutzky 博士和 Alan Saghatelian 博士都将指导首席研究员的科学 这一时期的发展。 Plutzky 博士是脂质转录调控领域的科学领导者 代谢和血管炎症具有既定的记录。普鲁茨基博士指导过其他人 学员在生物医学研究领域取得成功的职业生涯。 Saghatelian 博士是该领域公认的领导者 哈佛大学化学系脂质代谢组学和脂质化学研究室。在界面上 在化学和生物学之间，这个职业发展奖为化学和生物学创造了独特的培训环境 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/布莱根妇女医院血管生物学卓越中心是一所特殊的机构 提供无数资源的环境，以确保主要研究者成功实现 学术医学的独立职业。 我们提供了新的证据表明肝脂肪酶选择性激活过氧化物酶体增殖物激活 受体-¿ (PPAR¿) 通过 VLDL 水解产生脂肪酸进行体外和体内转录 代谢物。该数据构成了该提案的中心假设：肝脂肪酶选择性激活 PPAR¿ 依赖性转录，协调肝脏中的脂肪酸代谢。我们建议学习 肝脂肪酶介导的 PPAR 的机制以及转录和代谢后果¿ 体外和体内激活。具体目标是：（1）研究肝脂肪酶的分子基础—— 体外介导的 PPAR¿ 激活； (2) 确定肝脂肪酶介导的 PPAR¿ 激活在 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 脂肪酶功能获得和丧失技术以及肝细胞特异性 PPAR¿ 缺陷小鼠。一种理解 通过肝脂肪酶作用激活内源性 PPAR 对于 根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。