Role of FoxO1 in Lipid Metabolism

描述（由申请人提供）：候选人-本K99/R 00提案的总体目标是促进我从培训轨道（本科，博士和博士后）过渡到领导轨道作为一个完全独立的学术研究者。我对K99部分的目标是培养仍然缺乏但对我的研究目标是必要的技能，培养知识和初步数据的坚实基础，并获得终身助理教授职位。我已经制定了一个广泛的培训计划，以帮助我实现这些目标。这个计划包括学习新技术，课程，在当地和国际会议上展示我的工作，并学习成为一名导师。我将得到一个由资深研究人员组成的宝贵团队的指导，其中包括我的导师、三名科学顾问、三名外部合作者和一名职业发展顾问。我对R 00的目标是利用我独特的技能，这两个生物医学研究领域的桥梁，推出一个富有成效的和成功的实验室。在此期间，我计划招募学生和助手，收集数据，发表我的工作，在我的新环境中确定导师和顾问，发展新的合作，并申请R 01。作为一名学术研究者，我的长期职业目标是推进代谢疾病领域的知识，为患者开发新的医学治疗和诊断选择，培养高素质的研究人员，并与 在同一学科和其他学科的研究人员。环境-哥伦比亚大学是全国最好的学术机构之一，几乎任何措施。校园的生产力反映在它在联邦研究资金中的大学，学院和私立机构中排名第11。哥伦比亚大学医学系有着悠久的科学卓越历史，目前是与我的研究相关的领域的杰出研究人员的家园：脂质代谢，动脉粥样硬化，糖尿病和肥胖症。有了这个丰富的环境，我可以完全访问所有的资源来执行拟议的研究。我在哥伦比亚和其他地方的导师、顾问和合作者构成了这个提议的一个关键方面。在K99期间，我计划利用他们在科学和职业方面的专业知识和指导。心血管疾病（CVD）仍然是该国死亡和残疾的主要原因。现有的治疗方法是不够的，部分原因是它们不能纠正 许多CVD高危患者的主要缺陷。代谢综合征和糖尿病是CVD的两个主要危险因素，并且它们与加速动脉粥样硬化形成的脂质代谢异常的特征性星座相关，包括高血清甘油三酯、低高密度脂蛋白胆固醇（HDL-C）和肝脏脂肪积累，这些缺陷对当前的降血脂剂反应不良。了解这些缺陷的生理和分子机制将扩大动脉粥样硬化治疗和预防的目标库。然而，在我们的知识中存在一个关键的差距：我们不知道为什么甘油三酯升高和HDL-C福尔斯在代谢综合征的自然史下降。肝脏是关键的兴趣，因为它跨越葡萄糖和脂质代谢，并且已经清楚的是，“胰岛素抵抗”的概念不能解释存在于肝脏中的所有代谢缺陷。 肝脏我对探索驱动肝脏葡萄糖和脂质代谢的信号通路之间的非经典联系感兴趣，希望在CVD的治疗方法中招募新的参与者。在初步的数据，我证明了迄今为止未知的经典Akt-FoxO通路，胆汁酸（BA）的组成，和脂质合成之间的联系。为了研究这一途径，我提出了三个目标：在目标1中，我将研究BA受体FXR在连接FoxO依赖性转录与脂肪生成中的作用;在目标2中，我将研究氧化固醇受体LXR的需要以及胆固醇在这一过程中的作用;在目的3中，我将研究FoxO依赖性BA组合物对外周组织中细胞表面BA受体TGR 5活性的影响，作为脂质代谢受损的潜在肝外机制。这些数据将提供一个路线图，以设计新的治疗干预措施，在治疗血脂异常的快速增长的人口， 患有代谢综合症的人

DESCRIPTION (provided by applicant): 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 o 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.