Brown Remodeling of White Adipose Tissue by PPARgamma Deacetylation

PPARgamma 脱乙酰化对白色脂肪组织的棕色重塑

基本信息

批准号：
8581242
负责人：
Li Qiang
金额：
$ 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：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2015-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8581242
关键词：
2,4-thiazolidinedione Academic Medical Centers Acetylation Address Adipocytes Adipose tissue Adverse effects Affect Agonist Amino Acids Animals Antidiabetic Drugs Binding Biology Boston Brown Fat Cardiovascular system Communities Comorbidity Complex Data Deacetylase Deacetylation Deposition Development Diabetes Mellitus Doctor of Philosophy Dyslipidemias Energy Metabolism Environment Epidemic Faculty Fatty Liver Five-Year Plans Funding Gene Expression Profiling Genes Goals Histones Homeostasis Human In Vitro Infiltration Inflammatory Response Insulin Insulin Resistance Knock-in Mouse Knowledge Lead Ligands Liquid substance Lysine Mass Spectrum Analysis Mediating Medicine Mentors Metabolic Metabolic syndrome Metabolism Methods Methylation Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Nutrient Obesity Oncogenic Organ PPAR gamma Phase Phenocopy Phenotype Physiological Post-Translational Protein Processing Process Production Regulation Research Research Personnel Resistance Role Seminal Site Testing Therapeutic Therapeutic Agents Thermogenesis Thiazolidinediones Tissues Training Transferase Translating Triglycerides Universities Visceral Weight Gain adipokines adiponectin base bone loss cardiovascular risk factor career combat diabetic patient energy balance gain of function in vitro Model in vivo insight insulin sensitivity insulin sensitizing drugs macrophage medical schools member mimetics mutant novel novel therapeutics obesity treatment post-doctoral training prevent public health relevance response tool ward

项目摘要

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 Ppar? 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 Ppar?. 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 Ppar?-2KR mutant in vitro. Dr. Qiang proposes in this application (1) to characterize the physiological significance of Ppar? deacetylation, (2a) to determine the mechanism by which Ppar? 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 Ppar?'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 Ppar? 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 Ppar?, 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 Ppar? 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.

描述（由申请人提供）：该提案描述了李强转型为独立资助研究者的五年计划，将严格的科学方法应用于代谢研究。强博士于2007年在波士顿大学医学院获得博士学位，并自2008年起在糖尿病研究中心（DRC）和哥伦比亚大学医学系进行博士后研究。强博士的研究坚定了他揭示白色脂肪褐变机制的决心。通过 Ppar 组织（WAT）？脱乙酰化，并进一步导致治疗代谢综合征的新型治疗剂的发现。拟议培训的目标是为强博士提供培训和指导，为独立研究生涯做好准备，此外，还回答肥胖研究中持续存在的基本问题以及糖尿病患者的肥胖研究如何出错。肥胖会导致胰岛素抵抗并进一步导致 2 型糖尿病。目前可用的胰岛素增敏剂噻唑烷二酮类 (TZD) 因其有害作用而受到怀疑。最近，WAT 褐变因其代谢改善而受到赞赏。对 TZD 褐变功能的机制了解对于开发新的无副作用的抗糖尿病药物是必要的。在本申请中，Qiang 博士描述了初步数据，这些数据揭示了乙酰化在调节 Ppar? 转录选择性中的新作用。 Qiang 博士和他的一位导师 Domenico Accili 确定 SirT1 的功能获得与 Browning WAT 中的 TZD 相似。这些效应在体外由模拟脱乙酰化的 Ppar?-2KR 突变体重现。强博士在此申请中提出(1)表征Ppar的生理意义？脱乙酰化，（2a）确定Ppar的机制？脱乙酰化将能量储存的 WAT 转化为能量耗散的 BAT 样组织，并且 (2b) 研究乙酰化与其他翻译后修饰 (PTM) 在调节 Ppar? 转录选择性和代谢功能方面的相互作用。从这些拟议的研究中获得的结果应该会产生重要的见解，了解将白色脂肪组织重新编程为能量分散位点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出一类新的 Ppar？配体显示 TZD 的有益代谢作用，但没有心血管、致癌和骨质流失合并症。强博士的长期职业目标是通过 Ppar? 的 PTM 来了解棕色重塑 WAT 的机制，并进一步将实验室取得的开创性发现转化为肥胖和糖尿病的治疗方法。需要在分子水平和生理水平以及 Ppar 的许多复杂和技术方面整合褐变 WAT 的科学知识？ PTM 和 SirT1 生物学问题可以通过他选择的导师（Domenico Accili 博士和 Wei Gu）和合作者（Ira Goldberg 博士和 Yingming Zhao）得到最好的解决，他们都是受人尊敬的研究人员，重视指导年轻且有抱负的教员。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以及强博士成为独立研究者和学术代谢界富有成效的成员所需的所有设施和教师发展工具。