Role of FoxO1 in Lipid Metabolism

FoxO1 在脂质代谢中的作用

基本信息

批准号：
8803861
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/8803861
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. 项目总结/摘要候选人 K99/R00 提案的总体目标是促进我从培训轨道的过渡（本科生、博士生和博士后）作为完全独立的学术研究者进入领导轨道。我的 K99 部分的目标是培养我的研究目标仍然缺乏但必要的技能，培养丰富的知识基础和初步数据，并获得终身教授助理教授职位。我制定了广泛的培训计划来帮助我实现这些目标。该计划包括学习新技术、课程作业、在本地和国际会议上展示我的工作以及学习成为导师。我将受到一组宝贵的高级研究人员的指导，其中包括我的导师、三位科学顾问、三名外部合作者和一名职业发展顾问。我的 R00 目标是利用我独特的技能，连接生物医学研究的两个领域，推出富有成效且成功的项目实验室。在这段时间里，我计划招募学生和助理，收集数据，发表我的作品，确定在我的新环境中寻找导师和顾问，发展新的合作，并申请 R01。我的长- 作为学术研究者的职业目标是增进代谢疾病领域的知识，为患者开发新的医疗和诊断方案，培训高素质的研究人员，并与同一学科和其他学科的研究人员开展富有成效的合作。环境无论以何种标准衡量，哥伦比亚大学都是全国最好的学术机构之一。这校园生产力体现在其在大学、学院和私立机构中排名第 11 位在联邦研究经费中。哥伦比亚大学医学系拥有悠久的科学卓越历史，并且目前是与我的研究相关领域的杰出研究人员的家：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。我在哥伦比亚大学和其他地方的导师、顾问和合作者，是本提案的一个重要方面。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。现有的治疗方法不足，部分原因是它们无法纠正许多患者的主要缺陷 CVD 风险高。代谢综合征和糖尿病是心血管疾病的两大危险因素，与加速动脉粥样硬化形成的一系列脂质代谢异常特征相关，包括高血清甘油三酯、低高密度脂蛋白胆固醇（HDL-C）和积累肝脏脂肪，对当前降血脂药物反应不佳的缺陷。了解生理这些缺陷的分子机制将扩大动脉粥样硬化治疗的靶点和预防。然而，我们的知识存在一个关键差距：我们不知道为什么甘油三酯会升高， HDL-C 属于代谢综合征的自然史。肝脏至关重要，因为它跨越葡萄糖和脂质代谢，并且很明显“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脏葡萄糖和脂质代谢的信号通路之间的联系，希望招募新参与者参与 CVD 治疗方法。在初步数据中，我展示了迄今为止经典 Akt-FoxO 通路、胆汁酸 (BA) 组成和脂质合成之间的未知联系。到为了研究这条通路，我提出了三个目标：在目标 1 中，我将研究 BA 受体 FXR 在将 FoxO 依赖性转录与脂肪生成联系起来；在目标 2 中，我将调查以下要求：氧甾醇受体LXR以及胆固醇在此过程中的作用；在目标 3 中，我将研究 FoxO 的效果- BA 组成依赖于外周组织中细胞表面 BA 受体 TGR5 的活性，脂质代谢受损的潜在肝外机制。这些数据将提供设计路线图在快速增长的人口中治疗血脂异常的新治疗干预措施患有代谢综合症的人。