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

• 批准号: 9329411
• 负责人: Li Qiang
• 金额: $ 24.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2018-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329411
• 关键词: Academic Medical Centers; Acetylation; Address; Adipocytes; Adipose tissue; Adverse effects; Affect; Agonist; Amino Acids; 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; Genetic Transcription; Goals; Histone-Lysine N-Methyltransferase; Homeostasis; Human; In Vitro; Infiltration; Inflammatory Response; Insulin Resistance; Knowledge; Lead; Ligands; Liquid substance; Logistics; Lysine; Mass Spectrum Analysis; Mediating; Medicine; Mentors; Metabolic; Metabolic syndrome; Metabolism; Methods; Methylation; Methyltransferase; Molecular; 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; SIRT1 gene; Seminal; Site; Testing; Therapeutic; Therapeutic Agents; Thermogenesis; Thiazolidinediones; Tissues; Training; Translating; Triglycerides; Universities; Visceral; Weight Gain; adipokines; adiponectin; base; bone loss; cardiovascular risk factor; career; collaborative environment; combat; diabetic patient; energy balance; gain of function; in vitro Model; in vivo; insight; insulin sensitivity; insulin sensitizing drugs; knockin animal; macrophage; medical schools; member; mimetics; mutant; novel; novel therapeutics; obesity treatment; post-doctoral training; prevent; public health relevance; response; tool; ward

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.

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 年获得波士顿大学医学院博士学位，并于 2007 年获得博士学位。自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。强博士的培训坚定了他揭示白色脂肪组织褐变机制的决心通过 Pparγ 脱乙酰化（WAT），进一步发现治疗代谢综合征的新型治疗剂。拟议培训的目标是为强博士的独立研究生涯提供培训和指导，并回答问题。肥胖研究中持续存在的基本问题以及肥胖如何导致胰岛素抵抗和进一步的 2 型糖尿病。最近，WAT 的褐变因其代谢改善而受到赞赏，对于开发无副作用的新型抗糖尿病药物来说，有必要了解 TZD 的褐变功能。强博士描述了揭示乙酰化在调节 Pparγ 转录选择性中的新作用的初步数据。强博士和他的导师之一 Domenico Accili 确定了 SirT1。功能获得在褐变 WAT 中模拟 TZD。Qiang 博士在体外模拟了脱乙酰化 Pparγ-2KR 突变体，以表征 Pparγ 脱乙酰化的生理意义，(2a)。确定 Pparγ 脱乙酰化将能量储存 WAT 转化为能量耗散 BAT 样组织的机制，以及 (2b) 研究乙酰化和其他翻译后修饰 (PTM) 在调节 Pparγ 转录选择性和代谢功能中的相互作用从这些拟议研究中获得的结果应该能够为将白色脂肪组织重编程为能量分散位点是否将为该病提供新的治疗选择提供重要的见解。人类肥胖和糖尿病，以及是否有可能开发出一类新型 Pparγ 配体，该配体显示 TZD 的有益代谢作用，但不会导致心血管、致癌和骨质流失强博士的长期职业目标是通过 Pparγ 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整合棕色化所需的科学知识。分子水平和生理水平上的 WAT，以及 Pparγ PTM 和 SirT1 生物学的许多复杂和技术方面的问题，可以通过他选择的导师（Domenico 博士）得到最好的解决。 Accili 和 Wei Gu）以及合作者（Ira Goldberg 博士和赵英明）都是受人尊敬的研究人员，他们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多样化的代谢研究小组和所有设施。强博士成为独立研究者和代谢学术界富有成效的成员所需的教师发展工具。