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: 9121141
• 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/9121141
• 关键词: 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; Health; 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; collaborative environment; 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; 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（由适用提供）：该提案描述了李·齐安（Li Qiang）过渡到独立资助的研究者的五年计划，并将严格的科学方法应用于代谢研究。自2008年以来，Qiang博士于2007年获得波士顿大学医学院的博士学位，并在糖尿病研究中心（DRC）和医学系进行了博士学位培训。拟议的培训的目标是提供培训和心理，以准备Qiang博士为独立的研究职业做准备，此外，还可以回答肥胖研究中持续存在的基本问题，以及糖尿病患者如何出现问题。肥胖会导致胰岛素抵抗和进一步的2型糖尿病。目前可用的胰岛素传感器噻唑烷二酮（TZDS）对其有害影响表示怀疑。最近，WAT的布朗宁因其代谢改善而受到赞赏。对TZD褐变功能的机械理解对于开发新的抗糖尿病药物是副作用的新型抗糖尿病药物是必要的。在此应用中，Qiang博士描述了初步数据，这些数据揭示了乙酰化在确定PPARγ的转录选择性方面的新作用。 Qiang博士及其导师之一Domenico Accili确定SIRT1功能收益模仿Browning Wat中的TZD。这些作用在体外被脱乙酰化模拟PPARγ-2KR突变体概括。 Qiang博士在本应用中提出的建议（1）表征PPARγ脱乙酰基化的物理意义，（2a）确定PPARγ脱乙酰化将能量存储的机制转化为能量降低蝙蝠的能量的蝙蝠状组织，以及（2B）研究乙酰基化和其他转化后的互动率（2b），并将其互动（2b功能。从这些拟议的研究中得出的结果应产生重要的见解，即将重编程为能量分散部位的重编程是否会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新的PPARγ配体，这些PPARγ配体显示TZD的有益代谢作用，但没有心血管造成的，没有其心血管造成其心血管菌，Oncocenatigant，Oncenogenatigant，brotess and Comentic and Comentic and Comorbornities。 Qiang博士的长期职业目标是通过PPARγ的PTMS了解棕色重塑的WAT的机制，并进一步将替补席的第二个发现转化为肥胖和糖尿病的治疗方法。可以通过他选择的导师（Domenico Accili和Wei Gu博士）和合作者（Ira Goldberg and Yingming Zhao and Offerting and Offerting and Offerting and Offerting and Offerning anding Whor，都尊重所有校长，因此最好通过他的选择来解决分子水平和身体水平以及PPARγPTMS和SIRT1生物学的许多复杂和技术方面所需的科学知识，以及PPARγPTMS和SIRT1生物学的许多复杂和技术方面的科学知识。最后，哥伦比亚大学医学中心环境汇集了Qiang博士需要成为独立研究者和学术代谢社区的产品成员所需的潜水代谢研究小组以及所有设施和教师发展工具的机会。