Role of IRF3 in Energy and Glucose Homeostasis

IRF3 在能量和血糖稳态中的作用

基本信息

批准号：
10264168
负责人：
Evan D Rosen
金额：
$ 66.22万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10264168
关键词：
Ablation Accounting Address Adipocytes Adipose tissue Adverse effects Affect Antisense Oligonucleotides Area Body Weight Brown Fat Cellular biology Chronic Coupled Data Environment Family Fatty Liver Fatty acid glycerol esters Functional disorder Funding Gap Junctions Gene Expression Genes Genetic Transcription Genomics Glycolysis Goals Health Hepatocyte IRF3 gene ISG15 gene Immune Immune signaling Immunity Impairment Inflammation Inflammation Mediators Inflammatory Response Institutes Insulin Insulin Resistance Interferons Knowledge Kupffer Cells Laboratories Lead Link Liver Lysine Mediating Mediator of activation protein Metabolic Metabolic Control Metabolic dysfunction Metabolism Molecular Mus NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Obesity Overnutrition Pathway interactions Peripheral Phenocopy Phenotype Physiological Play Positioning Attribute Process Proteins Publishing Reagent Repression Research Personnel Resistance Resolution Role Signal Transduction Testing Therapeutic Therapeutic Intervention Thermogenesis Tissues Transcriptional Regulation Transgenes Tumor-infiltrating immune cells Ubiquitin Weight Gain Work blood glucose regulation cell type cytokine endophenotype enzyme activity epigenomics experimental study falls feeding human disease improved in vivo insulin sensitivity insulin signaling macrophage member programs response systemic inflammatory response tool transcription factor ubiquitin-protein ligase

项目摘要

ABSTRACT Obesity and Type 2 diabetes represent states of chronic inflammation. While we have learned much about how the soluble mediators and signaling intermediates of immunity disrupt normal metabolic function, we do not yet understand the transcriptional mechanisms by which these responses occur. Our laboratory has discovered that interferon regulatory factors (IRFs), a family of immune-related transcription factors, are active in tissues of metabolic relevance. We showed that IRF3 in particular becomes induced during obesity, and mediates many of the adverse effects of overnutrition, including weight gain, suppression of brown fat function, insulin resistance, and hepatic steatosis. We have gone on to show that IRF3 exerts distinct functions in adipocytes and hepatocytes, with differential effects on metabolic parameters. We also identify a key downstream IRF3 target, ISG15, as a mediator of the actions of IRF3 in fat. In the current proposal, we will advance our knowledge of IRF3 and metabolic function by focusing on its actions in macrophages, specifically in adipose tissue macrophages and Kupffer cells of the liver. Furthermore, we will determine the mechanisms by which ISG15 represses adipose browning and thermogenesis. Finally, we will pursue an unbiased analysis of IRF3 target genes in fat, liver, and macrophages, to determine new pathways at the nexus of metabolism and inflammation that may be amenable to therapeutic intervention.

抽象的肥胖和2型糖尿病代表慢性炎症的状态。虽然我们学会了关于免疫力的可溶性介质和信号中间体如何破坏正常状态代谢功能，我们尚不了解这些转录机制反应发生。我们的实验室发现干扰素调节因素（IRF），一个家庭免疫相关转录因子的活性在代谢相关性的组织中。我们展示了尤其是在肥胖期间诱导的IRF3，并介导许多不良反应营养不良，包括体重增加，抑制棕色脂肪功能，胰岛素抵抗和肝脂肪变性。我们继续表明，IRF3在脂肪细胞中发挥了不同的功能肝细胞，对代谢参数具有不同的影响。我们还标识下游的钥匙 IRF3靶标，ISG15，是IRF3脂肪作用的中介。在当前的建议中，我们将通过关注其在其中的行动来提高我们对IRF3和代谢功能的了解巨噬细胞，特别是肝脏巨噬细胞和肝脏的库普弗细胞。此外，我们将确定ISG15抑制脂肪褐变的机制和热生成。最后，我们将对脂肪，肝脏中的IRF3靶基因进行公正的分析，和巨噬细胞，以确定新陈代谢和炎症联系的新途径可能适合治疗干预。