Ubiquitin-dependent regulation of inflammation and insulin resistance

炎症和胰岛素抵抗的泛素依赖性调节

基本信息

批准号：
9243244
负责人：
VALENTINA PERISSI
金额：
$ 36.42万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243244
关键词：
Address Adipocytes Adipose tissue Adult Adverse effects American Anti-Inflammatory Agents Anti-inflammatory Antidiabetic Drugs Biological Assay Cardiovascular Diseases Cell Nucleus ChIP-on-chip ChIP-seq Chemicals Child Chromatin Chronic Disease Complex Cytoplasm Cytosol Data Deposition Development Diet Disease Energy Metabolism Enzymes Failure Fatty Liver Fatty acid glycerol esters G-substrate GPS2 gene GTP-Binding Proteins Gene Expression Gene Expression Profiling Gene Targeting Genes Genetic Genetic Transcription Goals Hand Health Homeostasis Human Imaging Techniques Impairment In Vitro Inflammation Inflammatory Inflammatory Response Insulin Resistance JNK-activating protein kinase MAPK8 gene Mediating Metabolic Metabolic Diseases Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity Overweight PPAR gamma Patients Phenotype Physiological Play Prevention Process Proteins Regulation Risk Factors Role Signal Transduction Stress TNF gene TRAF2 gene Testing Transcription Coactivator Transcriptional Regulation Transgenic Mice Ubiquitin United States Work adipokines base cofactor cytokine design diabetic experimental study histone demethylase in vivo inhibitor/antagonist innovation insulin sensitivity insulin signaling liver development macrophage mouse model novel novel strategies overexpression prevent public health relevance resistin response ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Obesity-associated inflammation is recognized as a critical factor in the development of insulin resistance leading to Type 2 diabetes and other metabolic disorders. However, the critical question of whether inhibiting inflammation is a good approach in the attempt to treat insulin resistance remains open. Our long-term goal is to investigate the endogenous regulatory mechanisms geared toward prevention of hyper-activation of inflammatory responses in the adipose tissue and to understand whether blunting inflammation may be partially counterproductive in maintaining insulin sensitivity. The rationale being that while the detrimental effects of pro-inflammatory cytokines are well known, there may be beneficial effects of inflammation that have been generally overlooked. G-protein Pathway Suppressor 2 (GPS2) is a transcriptional cofactor and an inhibitor of ubiquitin signaling playing an important anti-inflammatory role in the adipose tissue. This proposal is designed to: i) take advantage of the aP2-GPS2 mouse model to dissect the opposing effects of inhibiting inflammation in the context of obesity-induced insulin resistance; ii) uncover the molecular mechanism of GPS2 transcriptional actions as a novel coactivator of PPARγ. To address these questions, we propose three Aims: Specific Aim 1 will characterize the metabolic and inflammatory phenotype of the aP2-GPS2 transgenic mice and investigate the hypothesis that GPS2- mediated inhibition of inflammatory responses in adipocytes and macrophages impairs the storage capacity of the adipose tissue and induce ectopic fat deposition. Specific Aim 2 will dissect the molecular mechanism of GPS2-mediated transcriptional regulation of the adipokine gene resistin and broadly assess the relevance of GPS2 as a transcriptional coactivator in adipocytes. Specific Aim 3 will elucidate the structural basis of GPS2-mediated regulation of inflammatory responses via inhibition of specific ubiquitin machineries. Overall, the proposed studies will contribute significantly to the general understanding of the effects of inhibiting inflammatory responses on the regulation of the adipose tissue homeostasis and ectopic fat accumulation, and will define the molecular and structural basis of GPS2 transcriptional actions as a novel coactivator for the nuclear receptor PPARγ.

描述（由适用提供）：肥胖相关的炎症被认为是导致2型糖尿病和其他代谢性疾病的胰岛素抵抗发展的关键因素。但是，抑制炎症是否是治疗胰岛素抵抗的好方法仍然是开放的。我们的长期目标是研究旨在预防脂肪组织中炎症反应过度激活的内源性调节机制，并了解在维持胰岛素敏感性方面是否有部分适得其反。理由是，尽管促炎性细胞因子的有害作用是众所周知的，但炎症的有益作用通常被忽略了。 G蛋白途径抑制剂2（GPS2）是转录辅助因子和泛素信号抑制剂在脂肪组织中起重要的抗炎作用。该建议旨在：i）利用AP2-GPS2小鼠模型在肥胖引起的胰岛素抵抗的情况下剖析抑制感染的相反作用； ii）发现GPS2转录作用的分子机制是PPARγ的新型共激活因子。为了解决这些问题，我们提出了三个目的：具体目标1将表征AP2-GPS2转基因小鼠的代谢和炎症表型，并研究了GPS2介导的抑制脂肪细胞和巨噬细胞中炎症反应的抑制作用的假设会损害脂肪组织的储存能力和脂肪组织的储存能力，并诱导脂肪脂肪的脂肪。具体目标2将剖析脂肪因子基因抵抗素的GPS2介导的转录调节的分子机制，并广泛评估GPS2作为脂肪细胞中转录共激活剂的相关性。具体目标3将通过抑制特定的泛素计算机来阐明GPS2介导的炎症反应调节的结构基础。总体而言，拟议的研究将显着有助于对抑制炎症反应对脂肪组织稳态调节和生态脂肪积累的调节的影响的一般理解，并将GPS2转录作用的分子和结构基础作为核接收器PPARγ的新共聚因子的分子和结构基础。