Brown Remodeling of White Adipose Tissue by PPARgamma Deacetylation

内容（由申请人提供）：本提案描述了李强向独立科研人员过渡的五年计划，将严格的科学方法应用于代谢研究。2007年获波士顿大学医学院博士学位，2008年起在哥伦比亚大学糖尿病研究中心（DRC）和医学部进行博士后培训。Qiang博士的训练巩固了他通过Pparγ去乙酰化揭示白色脂肪组织（WAT）褐变机制的意图，并进一步导致发现治疗代谢综合征的新型药物。拟议培训的目标是为Qiang博士提供培训和指导，为独立的研究生涯做好准备，此外，回答肥胖研究中持续存在的基本问题，以及它如何在糖尿病患者中出错。肥胖会导致胰岛素抵抗和进一步的2型糖尿病。目前可用的胰岛素增敏剂噻唑烷二酮（TZDs）因其有害作用而受到怀疑。最近褐化的WAT因其改善代谢而受到重视。了解TZD褐变功能的机制，对于开发减少其副作用的新型抗糖尿病药物是必要的。在这一应用中，Qiang博士描述了初步数据，揭示了乙酰化在调节Pparγ转录选择性中的新作用。Qiang博士和他的导师之一Domenico Accili确定SirT1的功能获得与TZD在褐化WAT中的相似。这些效应在体外模拟去乙酰化的Pparγ-2KR突变体中得到了再现。Qiang博士在本申请中提出(1)表征Pparγ去乙酰化的生理意义，（2a）确定Pparγ去乙酰化将储存能量的WAT转化为耗散能量的bat样组织的机制，（2b）研究乙酰化和其他翻译后修饰（PTMs）在调节Pparγ转录选择性和代谢功能中的相互作用。从这些提议的研究中获得的结果应该对重新编程白色脂肪组织为能量分散位点是否会为人类肥胖和糖尿病提供新的治疗选择提供重要的见解，以及是否有可能开发一类新的Pparγ配体，显示TZD的有益代谢作用，但没有其心血管，致癌和骨质流失合并症。Qiang博士的长期职业目标是通过Pparγ的PTMs了解褐色重塑WAT的机制，并进一步将在实验台上取得的开创性发现转化为肥胖和糖尿病的治疗方法。在分子水平和生理水平上整合褐变WAT所需的科学知识，以及在Pparγ PTMs和SirT1生物学的许多复杂和技术方面，可以通过他选择的导师(dr。Domenico Accili和Wei Gu)及其合作者(dr .。Ira Goldberg和Yingming Zhao)，他们都是受人尊敬的研究者，重视指导年轻而有抱负的教师。最后，哥伦比亚大学医学中心的环境汇集了不同的代谢研究小组和所有的设施和教师发展工具，强博士将需要成为一个独立的研究者和学术代谢社区的富有成效的成员。

DESCRIPTION (provided by applicant): This proposal describes a five-year plan for Li Qiang to transition to an independently-funded investigator, applying rigorous scientific method to metabolic research. Dr. Qiang received PhD degree from Boston University School of Medicine in 2007 and performed postdoctoral training in Diabetes Research Center (DRC) and Department of Medicine at Columbia University since 2008. Dr. Qiang's training cemented his intent to uncover the browning mechanism of white adipose tissue (WAT) through Pparγ deacetylation, and further lead to the discovery of novel therapeutic agent to treat metabolic syndrome. The goals of the proposed training are to provide training and mentoring to prepare Dr. Qiang for an independent research career, and additionally, to answer fundamental questions that persist in obesity research and how it goes awry in diabetic patients. Obesity leads to insulin resistance and further Type 2 diabetes. Currently available insulin sensitizer thiazolidinediones (TZDs) are at skepticism for their detrimental effects. Recently browning of WAT has been appreciated for its metabolic improvement. A mechanistic understanding of the browning function of TZD is necessary to develop new anti-diabetic drugs that are shorn of the side effects. In this application, Dr. Qiang describes preliminary data that reveal the novel role f acetylation in regulating the transcriptional selectivity of Pparγ. Dr. Qiang and one of his mentors, Domenico Accili, determined that SirT1 gain-of-function mimics TZD in browning WAT. These effects were recapitulated by the deacetylation-mimetic Pparγ-2KR mutant in vitro. Dr. Qiang proposes in this application (1) to characterize the physiological significance of Pparγ deacetylation, (2a) to determine the mechanism by which Pparγ deacetylation converts energy-storing WAT into energy-dissipating BAT-like tissue, and (2b) to study the interplay between acetylation and other post-translational modifications (PTMs) in regulating Pparγ's transcriptional selectivity and metabolic functions. The results gained from these proposed studies should yield important insights into whether reprogramming white adipose tissue into an energy-dispersal site will provide new treatment options for human obesity and diabetes, and whether it is possible to develop a new class of Pparγ ligands that displays TZD's beneficial metabolic effects but without its cardiovascular, oncogenic, and bone loss comorbidities. Dr. Qiang's long-term career objective is to understand the mechanisms of brown remodeling WAT through PTMs of Pparγ, and further translate the seminal discoveries made at the bench into therapeutic treatments for obesity and diabetes. The scientific knowledge that required to integrate browning WAT at both molecular level and physiological level, as well as in the many complicated and technical aspects of Pparγ PTMs and SirT1 biology, can best be addressed through his choice of mentors (Drs. Domenico Accili and Wei Gu) and collaborators (Drs. Ira Goldberg and Yingming Zhao), all respected investigators who value mentoring young and aspiring faculty members. Finally, the Columbia University Medical Center environment brings together access to a diverse metabolic research groups and all the facilities and faculty developmental tools that Dr. Qiang will need in order to become an independent investigator and a productive member of the academic metabolism community.