Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism

项目总结/摘要 这个NIH指导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 在布里格姆妇女医院完成了心血管医学的临床研究，并将开始 一个研究计划，旨在培养一个独立的职业生涯中以疾病为导向的研究。校长 研究者将获得在转录、细胞生物学、代谢、脂质化学 化学分析方法，包括质谱法以及综合生理学研究， vivo. Jorge Plutzky博士和Alan Saghatelian博士将指导首席研究员的科学研究。 在此期间的发展。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，具有既定的跟踪记录。Plutzky博士指导了其他 学员成功的职业生涯中的生物医学调查。萨格特利安博士是该领域公认的领导者 在哈佛大学化学系从事脂质代谢组学和脂质化学的研究。的界面处 在化学和生物学之间，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。这一全面的计划描述将进一步加强合作的研究 四合院和化学系。作为该项目的主要地点，哈佛医学院 学校/布里格姆妇女医院卓越中心血管生物学是一个特殊的机构 环境提供无数的资源，以确保主要研究者的成功， 在学术医学中的独立职业。 我们提供了新的证据，肝脂肪酶选择性激活过氧化物酶体增殖物激活的 通过产生脂肪酸水解VLDL，在体外和体内进行受体-<$（PPAR <$）转录 代谢物。这个数据框架的核心假设，这一建议：肝脂肪酶选择性激活 在肝脏中协调脂肪酸代谢的PPAR-dependent转录。我们建议研究 肝脏脂肪酶介导的过氧化物酶体增殖物激活受体的机制及其转录和代谢结果 体外和体内活化。具体目的是：（1）研究肝脂酶的分子基础; （2）确定肝脏脂肪酶介导的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和肝细胞特异性PPAR γ缺陷小鼠。的理解 通过肝脂酶作用的内源性PPAR激活对 糖尿病和动脉粥样硬化等代谢功能障碍性疾病的发病机制。

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.