Role of FoxO1 in Lipid Metabolism

FoxO1 在脂质代谢中的作用

基本信息

批准号：
8836578
负责人：
Rebecca Anne Haeusler
金额：
$ 24.9万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-08 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8836578
关键词：
Ablation Agonist Area Atherosclerosis Bile Acid Biosynthesis Pathway Bile Acids Biochemical Biomedical Research Blood Brown Fat Carbon Cardiovascular Diseases Cause of Death Cell Surface Receptors Cell surface Cells Characteristics Cholesterol Collaborations Country Cyclic AMP Data Defect Development Diabetes Mellitus Diagnostic Diet Discipline Disease Doctor of Philosophy Dyslipidemias Energy Metabolism Environment Enzymes Face Fatty Acids Fatty acid glycerol esters Funding Gene Expression Generations Genes Genetic Epistasis Genetic Transcription Goals Hepatic Hepatocyte High Density Lipoprotein Cholesterol Home environment Homeostasis Hyperinsulinism Hyperlipidemia Hypertriglyceridemia Hypolipidemic Agents Indirect Calorimetry Institution Insulin Insulin Receptor Insulin Resistance International Knockout Mice Knowledge Laboratories Lead Leadership Learning Ligands Link Lipids Liver Measures Medical Medicine Mentors Metabolic Metabolic Diseases Metabolic syndrome Mitochondria Mixed Function Oxygenases Molecular Morphology Mus Natural History Nuclear Receptors Obesity Pathway interactions Patient Education Patients Peripheral Phase Phenotype Physiological Population Prevention Process Productivity Publishing Recording of previous events Recruitment Activity Regulation Relative (related person)Research Research Personnel Resources Risk Factors Role Science Serum Signal Pathway Signal Transduction Source Students Synthetic Genes Techniques Testing Therapeutic Time Tissues Training Transgenes Triglycerides United States Universities Up-Regulation Work abstracting activating transcription factor atherogenesis career career development chromatin immunoprecipitation college design disability falls feeding glucose metabolism glucose production high risk i-cholesterol improved insulin signaling interest knowledge base lipid biosynthesis lipid metabolism novel novel therapeutic intervention oxidation oxysterol binding protein receptor research study skills symposium transcription factor

项目摘要

7. Project Summary/Abstract Candidate The overall goal of this K99/R00 proposal is to facilitate my transition from a training track (undergraduate, PhD, and postdoctoral) to a leadership track as a fully independent academic investigator. My goals for the K99 component are to develop skills that are still lacking but necessary to my research goals, cultivate a substantial base of knowledge and preliminary data, and acquire a tenure-track assistant professorship. I have laid out an extensive training plan to help me achieve these goals. This plan includes learning new techniques, coursework, presenting my work at local and international conferences, and learning to be a mentor. I will be guided by an invaluable group of senior investigators, including my mentor, three scientific advisors, three external collaborators, and a career development advisor. My goals for the R00 are to use my unique skill set, which bridges two fields of biomedical research, to launch a productive and successful laboratory. During this time, I plan to recruit students and assistants, collect data, publish my work, identify mentors and advisors in my new environment, develop new collaborations, and apply for an R01. My long- term career goals as an academic investigator are to advance knowledge in the field of metabolic diseases, develop new medical treatment and diagnostic options for patients, train high quality investigators, and to develop fruitful collaborations with investigators in the same and other disciplines. Environment Columbia University is among the finest academic institutions nationwide, by almost any measure. The productivity on campus is reflected in its ranking as #11 among universities, colleges, and private institutions in federal research funding. Columbia's Department of Medicine has a long history of scientific excellence, and is currently home to outstanding investigators in the fields related to my research: lipid metabolism, atherosclerosis, diabetes, and obesity. With this rich environment, I have full access to all of the resources to perform the proposed research. My mentor, advisors, and collaborators, both at Columbia and elsewhere, constitute a crucial aspect of this proposal. During the K99, I plan to take advantage of their expertise and guidance, with regard to science and career. Research Cardiovascular disease (CVD) remains the leading cause of death and disability in the country. Available therapies are inadequate, in part because they fail to redress the primary defects in many patients at high risk for CVD. The metabolic syndrome and diabetes are two major risk factors for CVD, and they are associated with a characteristic constellation of lipid metabolic abnormalities that accelerate atherogenesis, including high serum triglycerides, low high-density lipoprotein cholesterol (HDL-C), and accumulation of liver fat, defects that are poorly responsive to current hypolipidemic agents. Understanding the physiological and molecular mechanisms of these defects will expand the repertoire of targets for atherosclerosis treatment and prevention. However, a crucial gap in our knowledge exists: we do not know why triglycerides rise and HDL-C falls in the natural history of the metabolic syndrome. The liver is of critical interest, because it straddles both glucose and lipid metabolism, and it has become clear that the notion of "insulin resistance" can not explain all of the metabolic defects present in the liver. I am interested in exploring non-canonical connections among signaling pathways that drive hepatic glucose and lipid metabolism, in the hope of enlisting new players in the therapeutic approach to CVD. In preliminary data, I demonstrate a heretofore unknown link between the canonical Akt-FoxO pathway, bile acid (BA) composition, and lipid synthesis. To investigate this pathway, I propose three aims: in Aim 1, I will examine the role of the BA receptor FXR in linking FoxO-dependent transcription with lipogenesis; in Aim 2, I will investigate the requirement for the oxysterol receptor LXR and the role of cholesterol in this process; and in Aim 3, I will study the effect of FoxO- dependent BA composition on the activity of the cell surface BA receptor, TGR5, in peripheral tissues, as a potential extra-hepatic mechanism of impaired lipid metabolism. These data will provide a roadmap to design new therapeutic interventions in the treatment of dyslipidemia within the rapidly growing population of people with the metabolic syndrome.

7。项目摘要/摘要候选人这个K99/R00建议的总体目标是促进我从训练轨道的过渡（本科，博士和博士后）作为完全独立的学术研究员的领导力轨道。我的 K99组件的目标是发展仍然缺乏但对我的研究目标所必需的技能，培养知识和初步数据的大量基础，并获得终身制助手教授职位。我制定了广泛的培训计划，以帮助我实现这些目标。该计划包括学习新技术，课程，在本地和国际会议上介绍我的工作以及学习成为一名导师。我将受到一群宝贵的高级调查员的指导，包括我的导师，三个科学顾问，三个外部合作者和一名职业发展顾问。我对R00的目标是使用我独特的技能集，桥接了两个生物医学研究领域，以推出一个富有成效的成功实验室。在此期间，我计划招募学生和助理，收集数据，发布我的作品，确定在我的新环境中的导师和顾问，开发新的合作并申请R01。我的长期作为学术研究者的职业生涯目标是促进代谢疾病领域的知识，为患者开发新的医疗和诊断选择，培训高质量的研究人员与同一学科的调查员建立富有成果的合作。环境哥伦比亚大学几乎是全国最好的学术机构之一。这校园的生产力反映在其排名第11的大学，大学和私人机构中在联邦研究资金中。哥伦比亚医学系具有悠久的科学卓越历史，并且目前是与我的研究有关的领域杰出调查员的所在地：脂质代谢，动脉粥样硬化，糖尿病和肥胖。有了这个丰富的环境，我可以完全访问所有资源进行拟议的研究。我在哥伦比亚和其他地方的导师，顾问和合作者构成该提议的关键方面。在K99期间，我计划利用他们的专业知识和关于科学和职业的指导。研究心血管疾病（CVD）仍然是该国死亡和残疾的主要原因。可用疗法不足，部分是因为它们无法纠正许多患者的主要缺陷 CVD的高风险。代谢综合征和糖尿病是CVD的两个主要危险因素，它们是与脂质代谢异常的特征星座相关，该星座加速了动脉粥样硬化，包括高血清甘油三酸酯，低密度脂蛋白胆固醇（HDL-C）和积累肝脏脂肪，对当前低脂药物反应不良的缺陷。了解生理这些缺陷的分子机制将扩大动脉粥样硬化治疗靶标的曲目和预防。但是，我们的知识存在一个关键差距：我们不知道为什么甘油三酸酯升高和 HDL-C属于代谢综合征的自然史。肝脏是关键的，因为它跨葡萄糖和脂质代谢，很明显，“胰岛素抵抗”的概念可以不能解释肝脏中存在的所有代谢缺陷。我有兴趣探索非规范驱动肝葡萄糖和脂质代谢的信号通路之间的连接，希望邀请新球员采用CVD的治疗方法。在初步数据中，我展示了一个迄今规范Akt-Foxo途径，胆汁酸（BA）组成和脂质合成之间的未知联系。到调查这一途径，我提出了三个目标：在AIM 1中，我将检查BA受体FXR的作用将依赖FOXO的转录与脂肪生成联系起来；在AIM 2中，我将调查对氧蛋白酶受体LXR和胆固醇在此过程中的作用；在AIM 3中，我将研究Foxo-的影响依赖性BA组成对外周组织中细胞表面Ba受体TGR5的活性，作为A 潜在的脂质代谢受损的肝外机理。这些数据将为设计提供路线图在迅速增长的人群中治疗血脂异常的新治疗干预措施患有代谢综合征的人。