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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：
10477318
负责人：
Evan D Rosen
金额：
$ 66.19万
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/10477318
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 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.

摘要