The zinc finger protein ZNF638 is a novel transcriptional regulator of thermogenesis - Resubmission

锌指蛋白 ZNF638 是一种新型产热转录调节因子 - Resubmission

• 批准号: 10063517
• 负责人: Elisabetta Mueller
• 金额: $ 43.47万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-17 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063517
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Architecture; Biological; Biological Process; Biology; Brown Fat; Calories; Cell physiology; Cells; Competence; Complex; Consumption; Cyclic AMP; DNA Binding; Data; Development; Diabetes Mellitus; Economic Burden; Energy Intake; Energy Metabolism; Equilibrium; Event; Expenditure; Family member; Fatty Liver; Fatty acid glycerol esters; Gene Expression; Gene Expression Regulation; Genetic; Genetic Transcription; Genomics; Health; Human; In Vitro; Knock-out; Laboratories; Lead; Leukocytes; Light; Link; Liver diseases; LoxP-flanked allele; Maintenance; Metabolic; Metabolic Diseases; Metabolic dysfunction; Molecular; Mus; Nuclear Matrix-Associated Proteins; Nutritional; Obesity; Output; Pathway interactions; Phenotype; Physiological; Physiology; Play; Property; Proteins; Publishing; RNA Recognition Motif; RNA Splicing; Reagent; Risk; Role; Signal Pathway; Signal Transduction; Societies; Stimulus; Techniques; Technology; Thermogenesis; Tissue Expansion; Tissues; Transcription Coactivator; Transcriptional Regulation; Transducers; Work; Zinc Fingers; adipocyte biology; adipocyte differentiation; adiponectin; blood glucose regulation; cofactor; cold temperature; combat; energy balance; experimental study; genome-wide; in vivo; insight; interest; mouse model; next generation sequencing; novel; novel therapeutics; obesity treatment; overexpression; promoter; protein protein interaction; response; subcutaneous; therapeutic target

PROJECT SUMMARY/ABSTRACT Obesity arises from an imbalance between the amount of energy stored and consumed and increases the risk of metabolic derangements, imposing significant economic burden to our society. Three types of fat cells -white, brown and beige- are critical for the maintenance of the equilibrium between calories hoarded and those utilized. Augmenting energy dissipation by boosting brown and beige fat thermogenesis has been proposed as a strategy to combat obesity; however, the current arsenal of proteins known to confer thermogenic competency to fat cells remains limited. Our laboratory has discovered that the zinc finger factor ZNF638 is a novel transcriptional regulator of adipocyte function. New work performed in our laboratory has now provided evidence demonstrating that mice lacking ZNF638 in fat tissue have weakened ability to withstand cold temperatures and increased propensity to obesity. Here we propose to assess the physiological role of ZNF638 in adipose tissues and to evaluate the consequences of loss- or gain-of-ZNF638-function on metabolic dysfunction. Furthermore, we plan to determine the molecular mechanisms that regulate ZNF638’s levels and functionality and through which ZNF638 coordinates transcriptional pathways regulating energy balance. At completion, the studies proposed will permit the detailing of ZNF638’s function in fat and the characterization of its upstream regulators, downstream target promoters and transcriptional partnerships, thereby clarifying its mechanism of action. To perform the work proposed we will take advantage of newly generated ZNF638 floxed mice and of molecular and cell biological techniques and reagents utilized in our laboratory over the years. These will be combined with unbiased approaches, as outlined in the aims below. In Aim 1 we will assess the physiological role of ZNF638 in the control of energy expenditure, glucose homeostasis and metabolic dysfunction through the characterization of adipose specific ZNF638 knock-out and overexpressing mice and will establish the genetic requirement and sufficiency of ZNF638 for beige and brown fat functionality; in Aim 2 we will identify the transcriptional and signaling pathways that regulate ZNF638 in adipose tissues and reveal the genome-wide targets of this cofactor in fat using state of the art next generation sequencing technologies. In addition we will define the molecular mechanisms through which ZNF638 regulates transcription in fat cells via the characterization of novel key transcriptional partners that enable ZNF638’s regulation of gene expression. We expect that the studies outlined will shed novel light into the mechanisms regulating energy balance and will ultimately permit the definition of new strategies to modulate energy metabolism with possible impact on the development of anti-obesity therapies.

项目摘要/摘要 肥胖是源于存储和消耗的能量数量之间的不平衡，并增加了风险 代谢进化，给我们的社会施加了巨大的经济负担。三种类型的脂肪细胞 - 白色， 棕色和米色 - 对于维持卡路里和那些卡路里之间的等效物至关重要 利用。已经提出，通过增强棕色和米色脂肪生热来增强能量耗散 打击肥胖的策略；但是，当前已知的热能能力已知的蛋白质武器库 脂肪细胞仍然有限。我们的实验室发现锌指因子Znf638是一种新颖 脂肪细胞功能的转录调节剂。在我们的实验室中进行的新工作现已提供 证明脂肪组织中缺乏ZnF638的小鼠的弱能力降低了冷的能力 温度和肥胖倾向的增加。在这里，我们建议评估Znf638的身体角色 在脂肪时机中，评估代谢损失或ZNF638功能的后果 功能障碍。此外，我们计划确定调节Znf638水平的分子机制和 功能和ZnF638协调调节能量平衡的转录途径。 完成的研究将允许详细介绍Znf638在脂肪中的功能和表征 它的上游监管机构，下游目标启动子和转录合作伙伴关系，从而澄清其 作用机理。为了执行提议的工作，我们将利用新生成的Znf638 Floxed 多年来，我们的实验室中使用的小鼠以及分子和细胞生物学技术和试剂。 这些将与公正的方法结合在一起，如下所述。在AIM 1中，我们将评估 ZnF638在能量消耗，葡萄糖稳态和代谢中的生理作用 通过脂肪特异性Znf638敲除和过表达的小鼠的表征的功能障碍 将确定Znf638对米色和棕色脂肪功能的遗传需求和充分性；在目标2中 我们将确定调节脂肪组织中Znf638的转录和信号通路并揭示 该辅助因子在脂肪中使用下一代测序技术在脂肪中的全基因组靶标。在 此外，我们还将定义Znf638通过该机制调节脂肪细胞中的转录 新型关键转录伙伴的表征能够使ZnF638的基因表达调节。 我们期望所概述的研究将把新颖的光放在调节能量平衡的机制中，并将 最终允许定义新策略来调节能源代谢，并可能影响 抗肥胖疗法的发展。