Novel mechanisms regulating adipose tissue function in health and disease

调节健康和疾病中脂肪组织功能的新机制

基本信息

批准号：
10736765
负责人：
Elisabetta Mueller
金额：
$ 47.12万
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：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736765
关键词：
ADORA2A gene Ablation Adenosine Adipocytes Adipose tissue Affect Aging Animal Model Biology Calories Cell secretion Cells Chromatin Conditioned Culture Media Consumption Cues Data Development Disease Energy Intake Epigenetic Process Equilibrium Expenditure Fatty acid glycerol esters Genes Genetic Transcription HSF1 Health Heat shock factor Heat-Shock Response Homeostasis Human Knockout Mice Knowledge Laboratories Learning Link Mediating Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Molecular Molecular Target Mus Nutrient availability Nutritional Obesity Output Pathologic Pathway interactions Physiological Process Publishing Reagent Regulation Risk Factors Role Signal Transduction Stimulus Stress Techniques Technology Temperature Thermogenesis Time Tissue Expansion Tissues Transgenic Animals Work adipocyte biology chromatin remodeling cofactor combat energy balance exosome fighting genome-wide histone demethylase innovation insight interest lipidomics new therapeutic target next generation sequencing novel novel strategies novel therapeutic intervention novel therapeutics promoter proteotoxicity response therapeutic target tool treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Excessive adipose tissue expansion causes obesity, a major risk factor for the development of metabolic disease. Three types of fat cells exist -white, brown and beige- involved in maintaining the balance between calories hoarded and those consumed. It has been recently suggested that increasing energy dissipation via the induction of thermogenesis in brown and beige adipocytes could represent a strategy to combat metabolic disease; however, at the present time, our understanding of the key targetable regulators involved in this process is still limited. My laboratory has identified the heat shock factor HSF1 as a novel transcriptional regulator of thermogenesis and has preliminary evidence demonstrating that HSF1 regulates histone demethylases, that obesity is associated with low levels of HSF1 and that ablation of HSF1 in fat leads to metabolic dysfunction. Based on this knowledge, we propose to determine how fat tissue is epigenetically reprogrammed in obese states and identify new molecular mechanisms controlling adipose tissue biology through the analysis of novel upstream regulators and downstream effectors of HSF1 in fat. The results of our studies will identify novel regulatory mechanisms controlling adipose tissue biology and specific epigenetic signatures contradistinctive of obese fat, identify HSF1 is a novel molecular link between extrinsic stimuli and transcriptional and epigenetic re- programming of adipose tissue, and a possible new therapeutic target for the treatment of metabolic dysfunction. To perform the studies outlined we will take advantage of unique fat specific HSF1- and adenosine receptor A2A knock-out mice generated in our laboratory and of techniques and reagents generated over the years and more innovative ones. In Aim 1 will identify novel chromatin signatures in adipose tissues associated with obesity and will assess the role of HSF1 in the epigenetic control of adipose tissue biology and homeostasis; in Aim 2 we will characterize novel regulators of adipocyte biology through the identification of new molecular targets of HSF1 in adipocytes, using state-of-the-art next generation sequencing technologies, in addition to candidate approaches; in Aim 3 we will identify novel pathways regulating innate thermogenesis in fat cells. We expect that the studies outlined will illuminate novel mechanisms that control energy balance in physiological and pathological metabolic states and will define new approaches to increase energy dissipation and combat metabolic disease.

项目概要/摘要脂肪组织过度扩张导致肥胖，这是代谢性心脏病发生的主要危险因素疾病。存在三种类型的脂肪细胞 - 白色、棕色和米色 - 参与维持之间的平衡储存的卡路里和消耗的卡路里。最近有人建议通过增加能量耗散棕色和米色脂肪细胞产热的诱导可能是对抗代谢的策略疾病;然而，目前我们对参与这一过程的关键目标监管机构的了解仍然有限。我的实验室已确定热休克因子 HSF1 是一种新型转录调节因子生热作用，并有初步证据表明 HSF1 调节组蛋白去甲基化酶，肥胖与 HSF1 水平低有关，脂肪中 HSF1 的消除会导致代谢功能障碍。基于这些知识，我们建议确定脂肪组织如何在肥胖者中进行表观遗传重编程通过分析新的分子机制，阐明并确定控制脂肪组织生物学的新分子机制脂肪中 HSF1 的上游调节因子和下游效应因子。我们的研究结果将确定新颖的控制脂肪组织生物学和特定表观遗传特征的调节机制肥胖脂肪，确定 HSF1 是外部刺激与转录和表观遗传修饰之间的一种新型分子联系脂肪组织的编程，以及治疗代谢功能障碍的可能的新治疗靶点。为了进行概述的研究，我们将利用独特的脂肪特异性 HSF1 和腺苷受体 A2A 我们实验室产生的基因敲除小鼠以及多年来产生的技术和试剂创新的。目标 1 将鉴定与肥胖相关的脂肪组织中的新染色质特征将评估 HSF1 在脂肪组织生物学和稳态的表观遗传控制中的作用；在目标 2 中，我们将通过鉴定 HSF1 的新分子靶标来表征脂肪细胞生物学的新型调节剂在脂肪细胞中，除了候选基因外，还使用最先进的下一代测序技术方法；在目标 3 中，我们将确定调节脂肪细胞先天产热的新途径。我们期望概述的研究将阐明控制生理能量平衡的新机制和病理代谢状态，并将定义增加能量耗散和对抗的新方法代谢性疾病。