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

基本信息

批准号：
10304195
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-17 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304195
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 acid glycerol esters Gene Expression Gene Expression Regulation Genetic Genetic Transcription Genomics Health Human In Vitro Knock-out Laboratories Lead Leukocytes Light Link 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 fatty liver disease 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

项目摘要

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.

项目概要/摘要肥胖是由于能量储存和消耗之间的不平衡引起的，并增加了风险代谢紊乱，给我们的社会带来了巨大的经济负担——白色、棕色和米色——对于维持储存的卡路里与摄入的卡路里之间的平衡至关重要已提出通过促进棕色和米色脂肪产热来增强能量耗散。对抗肥胖的策略；然而，目前已知具有产热能力的蛋白质库我们的实验室发现锌指因子 ZNF638 是一种新型因子。我们实验室进行的新工作现已提供脂肪细胞功能的转录调节因子。有证据表明脂肪组织中缺乏ZNF638的小鼠抵御寒冷的能力减弱温度和肥胖倾向增加在此我们建议评估 ZNF638 的生理作用。脂肪组织中的 ZNF638 功能的丧失或获得对代谢的影响此外，我们计划确定调节 ZNF638 水平和功能的分子机制。 ZNF638 通过其协调调节能量平衡的转录途径。完成后，拟议的研究将允许详细说明 ZNF638 在脂肪中的功能和表征其上游调节因子、下游目标启动子和转录伙伴关系，从而阐明其为了执行建议的工作，我们将利用新生成的 ZNF638 floxed。小鼠以及我们实验室多年来使用的分子和细胞生物技术和试剂。这些将与公正的方法相结合，如下面的目标 1 中所述，我们将评估： ZNF638 在控制能量消耗、葡萄糖稳态和代谢中的生理作用通过脂肪特异性 ZNF638 敲除和过表达小鼠的表征来发现功能障碍将确定目标 2 中米色和棕色脂肪功能的 ZNF638 的遗传要求和充足性；我们将鉴定脂肪组织中调节 ZNF638 的转录和信号传导途径，并揭示使用最先进的下一代测序技术来确定脂肪中该辅因子的全基因组目标。此外，我们将通过 ZNF638 调节脂肪细胞转录的分子机制使 ZNF638 能够调节基因表达的新型关键转录伙伴的表征。我们期望概述的研究将为调节能量平衡的机制提供新的启示，并将最终允许定义新的策略来调节能量代谢，并可能对抗肥胖疗法的发展。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The forkhead box transcription factor FoxP4 regulates thermogenic programs in adipocytes.

叉头盒转录因子 FoxP4 调节脂肪细胞中的产热程序。

DOI：
发表时间：
2021
期刊：
影响因子：
6.5
作者：
Perie, Luce;Verma, Narendra;Mueller, Elisabetta
通讯作者：
Mueller, Elisabetta

Browning of adipose tissue and increased thermogenesis induced by Methotrexate.

甲氨蝶呤诱导脂肪组织褐变和生热作用增加。

DOI：
发表时间：
2021-11
期刊：
影响因子：
2.7
作者：
Verma, Narendra;Perie, Luce;Corciulo, Carmen;Leucht, Philipp;Ramkhelawon, Bhama;Cronstein, Bruce N;Mueller, Elisabetta
通讯作者：
Mueller, Elisabetta

Transcriptional Regulation of ZNF638 in Thermogenic Cells by the cAMP Response Element Binding Protein in Male Mice.

雄性小鼠中 cAMP 响应元件结合蛋白对产热细胞中 ZNF638 的转录调节。