Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism

肝脂肪酶、PPAR-δ 和脂肪酸代谢

• 批准号: 8029238
• 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/8029238
• 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; 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; 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

DESCRIPTION (provided by applicant): 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-4 (PPAR4) 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 PPAR4 -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 PPAR4 activation in vitro and in vivo. The specific aims are: (1) to study the molecular basis of hepatic lipase- mediated PPAR4 activation in vitro; (2) to determine the role of hepatic lipase-mediated PPAR4 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 PPAR4 deficient mice. An understanding of endogenous PPAR4 activation through hepatic lipase action has fundamental implications for the pathogenesis of diseases rooted in metabolic dysfunction including diabetes mellitus and atherosclerosis. PUBLIC HEALTH RELEVANCE: The epidemics of diabetes mellitus and metabolic disorders such as obesity are a major cause of heart disease and death in the Western world. This proposal studies how PPARs, a family of proteins that control metabolism in humans, are regulated. Better insight into how PPARs work will identify new ways to treat metabolic diseases with the goal of improving public health.

描述（由申请人提供）：这份 NIH 指导临床科学家研究职业发展奖提案描述了学术心血管医学职业发展的五年培训计划。首席研究员已在布莱根妇女医院完成了心血管医学临床研究，并将开展一项研究计划，旨在培训以疾病为导向的研究的独立职业。主要研究人员将在转录、细胞生物学、代谢、脂质化学和化学分析方法（包括质谱法）以及体内综合生理学研究方面获得深入的经验。 Jorge Plutzky 博士和 Alan Saghatelian 博士将在此期间指导首席研究员的科学发展。 Plutzky 博士是脂质代谢和血管炎症转录调控领域的科学领导者，拥有良好的记录。 Plutzky 博士指导其他学员在生物医学研究领域取得了成功的职业生涯。 Saghatelian 博士是哈佛大学化学系脂质代谢组学和脂质化学领域的知名领导者。该职业发展奖位于化学和生物学的交叉点，为申请人创造了独特的培训环境。该综合计划将通过研究四方和化学系的合作进一步加强。作为该项目的主要地点，哈佛医学院/布莱根妇女医院血管生物学卓越中心拥有特殊的机构环境，提供无数资源，以确保主要研究者在学术医学领域的独立职业生涯中取得成功。我们提供了新的证据，证明肝脂肪酶通过 VLDL 水解产生脂肪酸代谢物，在体外和体内选择性激活过氧化物酶体增殖物激活受体 4 (PPAR4) 转录。该数据构成了该提议的中心假设：肝脂肪酶选择性激活 PPAR4 依赖性转录，协调肝脏中的脂肪酸代谢。我们建议在体外和体内研究肝脂肪酶介导的 PPAR4 激活的机制以及转录和代谢后果。具体目的是：（1）体外研究肝脂肪酶介导的PPAR4激活的分子基础； (2)确定肝脂肪酶介导的PPAR4激活在肝细胞脂肪酸代谢转录和功能调节中的作用。这些研究将利用肝脂肪酶功能获得和丧失技术以及肝细胞特异性 PPAR4 缺陷小鼠。了解通过肝脂肪酶作用激活内源性 PPAR4 对于糖尿病和动脉粥样硬化等代谢功能障碍疾病的发病机制具有重要意义。 公共卫生相关性：糖尿病和肥胖等代谢紊乱的流行是西方世界心脏病和死亡的主要原因。该提案研究了 PPAR（控制人类新陈代谢的蛋白质家族）是如何受到调节的。更好地了解 PPAR 的工作原理将找到治疗代谢疾病的新方法，从而改善公众健康。