Brown Remodeling of White Adipose Tissue by PPARgamma Deacetylation

描述(申请人提供)：本提案描述了李强向独立资助的研究人员过渡的五年计划，将严谨的科学方法应用于代谢研究。强博士2007年获得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)和医学系进行博士后培训。强博士的培训巩固了他通过PPARγ去乙酰化来揭示白色脂肪组织(WAT)褐变机制的意图，并进一步导致了治疗代谢综合征的新型治疗剂的发现。拟议中的培训的目标是提供培训和指导，为强博士的独立研究生涯做好准备，此外，还将回答肥胖研究中持续存在的基本问题，以及糖尿病患者的研究是如何出错的。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(TZD)对其有害影响持怀疑态度。最近，Wat的褐变因其改善新陈代谢而受到赞赏。从机理上了解TZD的褐变功能对于开发无副作用的抗糖尿病新药是必要的。在这项申请中，强博士描述了初步数据，揭示了乙酰化在调节PPARγ转录选择性方面的新作用。强博士和他的一位导师多梅尼科·阿奇利确定，SirT1的功能增益模仿了Browning Wat中的TZD。这些效应在体外被模拟脱乙酰化的PPARγ-2KR突变体概括。在这一应用中，强博士建议(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转化为类似蝙蝠的能量组织的机制，以及(2b)研究乙酰化和其他翻译后修饰(PTM)在调节PPARγ的转录选择性和代谢功能中的相互作用。从这些拟议的研究中获得的结果将为以下方面提供重要的见解：将白色脂肪组织重新编程到能量分散位置是否将为人类肥胖和糖尿病提供新的治疗选择，以及是否有可能开发一类新的PPARγ配体，该配体显示出TZD的有益代谢作用，但没有其心血管、致癌和骨丢失的共病。强博士的长期职业目标是通过PPARγ的PTMS了解棕色重塑WAT的机制，并进一步将该工作台上的开创性发现转化为肥胖症和糖尿病的治疗方法。在分子水平和生理水平整合Browning Wat所需的科学知识，以及在PPARγPTMS和SirT1生物学的许多复杂和技术方面所需的科学知识，最好通过他选择的导师(Domeico Accili博士和魏谷博士)和合作者(Ira Goldberg博士和赵英明博士)来解决，他们都是受人尊敬的研究人员，他们都重视指导年轻和有抱负的教职员工。最后，哥伦比亚大学医学中心的环境汇集了各种代谢研究小组以及所有设施和教师发展工具，这是强博士成为一名独立研究员和学术新陈代谢社区富有成效的成员所需的。

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.