Role of FoxO1 in Lipid Metabolism

申请人描述：候选人-K99/R00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，成为一名完全独立的学术研究人员。我对K99课程的目标是发展仍然缺乏但对我的研究目标来说是必要的技能，培养坚实的知识和初步数据基础，并获得终身教职助理教授的职位。我已经制定了一个广泛的培训计划来帮助我实现这些目标。这项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，以及学习成为一名导师。我将得到一组宝贵的高级调查人员的指导，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R00的目标是使用我的独特技能集，这套技能连接了生物医学研究的两个领域，以启动一个富有成效和成功的实验室。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R01。作为一名学术研究人员，我的长期职业目标是增进代谢性疾病领域的知识，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调查人员。环境--从几乎任何标准来看，哥伦比亚大学都是全美最好的学术机构之一。校园的生产力体现在它在大学、学院和私立机构中的联邦研究经费排名中排名第11。哥伦比亚大学医学部有着悠久的科学卓越历史，目前拥有与我的研究相关的领域的杰出研究人员：脂代谢、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资源来执行拟议的研究。我在哥伦比亚大学和其他地方的导师、顾问和合作者构成了这项提案的关键方面。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。研究-心血管疾病(CVD)仍然是该国死亡和残疾的主要原因。现有的治疗方法是不够的，部分原因是它们未能纠正 许多患者的原发缺陷是心血管疾病的高危人群。代谢综合征和糖尿病是心血管疾病的两个主要危险因素，它们与一系列加速动脉粥样硬化形成的脂代谢异常有关，包括高血清甘油三酯、低高密度脂蛋白胆固醇(HDLC)和肝脏脂肪堆积，这些缺陷对目前的降血脂药物反应较差。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靶点。然而，我们的知识中存在一个关键的缺口：我们不知道为什么在代谢综合征的自然历史中，甘油三酯上升而高密度脂蛋白胆固醇下降。肝脏是至关重要的，因为它横跨葡萄糖和脂肪代谢，而且很明显，“胰岛素抵抗”的概念不能解释存在于体内的所有代谢缺陷。 肝脏。我对探索驱动肝脏葡萄糖和脂肪代谢的信号通路之间的非典型联系感兴趣，希望在心血管疾病的治疗方法中招募新的参与者。在初步数据中，我展示了一个迄今未知的联系，在经典的Akt-FoxO途径，胆汁酸(BA)的组成，和脂质合成。为了探索这一途径，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依赖的转录和脂肪生成中的作用；在目标2中，我将研究对氧固醇受体LXR的需求和胆固醇在这一过程中的作用；在目标3中，我将研究依赖FoxO的BA组成对细胞表面BA受体TGR5活性的影响，作为脂质代谢受损的潜在肝外机制。这些数据将为设计新的治疗干预措施在快速增长的中国人口中治疗血脂异常提供路线图。 患有代谢综合征的人。

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.