Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism

肝脂肪酶、PPAR-δ 和脂肪酸代谢

基本信息

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
项目类别：
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

项目摘要

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）：这项NIH指导的临床科学家研究职业发展奖提案描述了一项为期五年的学术心血管医学培训计划。这位原则研究者已在Brigham和妇女医院完成了心血管医学的临床奖学金，并将着手进行一项研究计划，旨在培训以疾病为导向的研究的独立职业。首席研究者将在转录，细胞生物学，代谢，脂质化学和化学分析方法方面获得深入的经验，包括质谱以及体内综合的生理研究。豪尔赫·普鲁茨基（Jorge Plutzky）博士和艾伦·萨加特利安（Alan Saghatelian）博士都将指导这位首席研究者的科学发展。 Plutzky博士是脂质代谢和血管炎症的转录调节的科学领导者，并具有既定的记录。 Plutzky博士已指导其他学员，从事生物医学调查的成功职业。 Saghatelian博士是哈佛大学化学系的脂质代谢组学和脂质化学领域的著名领导者。在化学与生物学之间的界面上，该职业发展奖为申请人创造了独特的培训环境。研究四边形和化学系的合作将进一步增强所描述的全面计划。作为该项目的主要地点，哈佛医学院/杨百翰和妇女医院血管生物学卓越中心是一个杰出的机构环境，提供了无数资源，以确保主要研究者在学术医学领域独立职业的成功。我们提供了新的证据表明，肝脂肪酶通过产生脂肪酸代谢物在体外和体内选择性地激活过氧化物酶体增殖物激活的受体-4（PPAR4）转录。该数据构成了该提案的中心假设：肝脂肪酶选择性激活了依赖PPAR4的转录，该转录可以协调肝脏中的脂肪酸代谢。我们建议研究肝脂肪酶介导的PPAR4在体外和体内的机制和转录和代谢后果。具体目的是：（1）研究体外肝脂肪酶介导的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的转录和功能调节中的作用。这些研究将利用肝脂肪酶的增益和功能丧失技术以及肝细胞特异性PPAR4缺陷小鼠。通过肝脂肪酶作用对内源性PPAR4激活的理解对植根于包括糖尿病和动脉粥样硬化在内的代谢功能障碍的疾病的发病机理具有根本性的影响。公共卫生相关性：糖尿病和肥胖症等代谢疾病的流行病是西方世界心脏病和死亡的主要原因。该建议研究如何调节PPARS（控制人类代谢的蛋白质家族）。更好地了解PPARS的工作方式将确定治疗代谢疾病的新方法，以改善公共卫生。