The Role and Mechanism of NLRX1-mediated Cell Stress Response in Insulin Resistan

NLRX1介导的细胞应激反应在胰岛素抵抗中的作用及机制

• 批准号: 8629738
• 负责人: Haitao Wen
• 金额: $ 15万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629738
• 关键词: Acute; Adipose tissue; Animal Model; Antimycin A; Apoptosis; Attenuated; Bile Acids; Binding; Biochemical; Bone Marrow; Butyric Acids; Cells; Cellular Stress; Chemicals; Chimera organism; Chronic; Complex; Cre-LoxP; Data; Defect; Development; Diabetes Mellitus; Diet; Disease; Endoplasmic Reticulum; Fatty acid glycerol esters; Functional disorder; Generations; Genetic; Glucose tolerance test; Goals; Health; Hematogenous; Hematopoietic; Hematopoietic System; Human; Image Analysis; Immune response; Immune system; Immunoblotting; Impairment; Incidence; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interferons; Interleukin-6; Knockout Mice; Lead; Leptin; Leptin deficiency; Leucine-Rich Repeat; Link; Liver; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Microbe; Mitochondria; Modeling; Molecular; Molecular Chaperones; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obesity; Oxidative Stress; Pathogenesis; Pathway interactions; Pattern; Phenotype; Play; Prevention; Production; Protein Family; Reactive Oxygen Species; Recruitment Activity; Regulation; Respiratory Chain; Reverse Transcriptase Polymerase Chain Reaction; Role; Rotenone; Signal Pathway; Signal Transduction; System; TNF receptor-associated factor 6; Testing; Tissues; Tunicamycin; Ubiquitination; Virus Diseases; base; biological adaptation to stress; cytokine; diabetic; endoplasmic reticulum stress; environmental stressor; feeding; global health; glucose metabolism; in vivo; inhibitor/antagonist; insight; insulin sensitivity; insulin signaling; insulin tolerance; intravenous injection; leucine-rich repeat protein; new therapeutic target; novel; nutrition; public health relevance; receptor; stressor; tauroursodeoxycholic acid; treatment strategy

DESCRIPTION (provided by applicant): The incidence of chronic metabolic diseases such as obesity and diabetes has increased dramatically and constitutes one of the major threats to global health. Recent studies have indicated that cell stress response plays an essential role in the pathogenesis of type 2 diabetes (T2D). Oxidative stress and endoplasmic reticulum (ER) stress cooperatively promote cell dysfunction, apoptosis and insulin resistance. While the activators and downstream effects of cell stress have been partially characterized, much is unknown regarding the molecular mechanisms by which the cell stress responses are regulated. Our lab and others have recently characterized the NLR (NBD-LRR) family of proteins, which have been shown to mediate the cell stress response to microbes and environmental stressors. My preliminary data indicates that NLRX1, a mitochondria-localized NLR protein, promotes ER stress response by mediating the generation of mitochondrial reactive oxygen species (mROS). Mechanistically, NLRX1 directly associates with ECSIT (evolutionarily conserved signaling intermediate in Toll pathways) and TRAF6 (TNF receptor-associated factor 6), both of which are important in mitochondrial respiratory chain assembly. NLRX1-deficient (Nlrx1-/-) cells are protected from ER stress-inhibited insulin-PI3K-Akt pathway. Moreover, Nlrx1-/- mice were protected from obesity- induced insulin resistance by high-fat diet (HFD) feeding. Therefore, I hypothesize that NLRX1 mediates mROS generation by facilitating ECSIT-TRAF6 function, which subsequently promotes ER stress, and that the NLRX1-mediated cell stress responses impair insulin signaling in insulin target tissues. I will employ T2D (HFD feeding and leptin-deficient ob/ob mice) animal models to examine the function of NLRX1-mediated cell stress responses in insulin resistance. I will examine how NLRX1 controls ECSIT function and mROS generation. The goal of the proposal is to examine the mechanism of the interaction between NLRX1-mediated oxidative stress and ER stress in promoting cell dysfunction and a defect in insulin signaling. The proposed genetic and biochemical analyses and animal model studies will provide novel insights into the regulation and function of metabolic signaling pathways. Further studies could lead to the identification of new therapeutic targets and ultimately help develop rational, mechanism-based treatment strategies that target obesity and diabetes.

描述(申请人提供)：肥胖和糖尿病等慢性代谢性疾病的发病率急剧增加，构成对全球健康的主要威胁之一。最近的研究表明，细胞应激反应在2型糖尿病(T2D)的发病机制中起着重要作用。氧化应激和内质网应激共同促进细胞功能障碍、细胞凋亡和胰岛素抵抗。虽然细胞应激的激活剂和下游效应已经被部分描述，但关于调节细胞应激反应的分子机制还不清楚。我们的实验室和其他人最近表征了NLR(NBD-LRR)蛋白质家族，这些蛋白质被证明介导细胞对微生物和环境应激源的应激反应。我的初步数据表明，NLRX1是一种线粒体定位的NLR蛋白，通过介导线粒体活性氧物种(MRO)的产生来促进内质网应激反应。在机制上，NLRX1直接与ECSIT(进化上保守的Toll通路信号中间体)和TRAF6(肿瘤坏死因子受体相关因子6)结合，这两个因子在线粒体呼吸链组装中都是重要的。NLRX1缺陷(NLRX1-/-)细胞受到内质网应激抑制的胰岛素-PI3K-Akt通路的保护。此外，NLRX1-/-小鼠通过高脂饮食(HFD)喂养保护免受肥胖诱导的胰岛素抵抗。因此，我假设NLRX1通过促进ECSIT-TRAF6功能而介导MRO的产生，从而促进内质网应激，并且NLRX1介导的细胞应激反应损害了胰岛素靶组织中的胰岛素信号转导。我将使用T2D(HFD喂养和瘦素缺乏的ob/ob小鼠)动物模型来研究NLRX1介导的细胞应激反应在胰岛素抵抗中的作用。我将研究NLRX1如何控制ECSIT功能和MRO生成。该提案的目的是研究NLRX1介导的氧化应激和内质网应激在促进细胞功能障碍和胰岛素信号缺陷方面的相互作用机制。拟议的遗传和生化分析以及动物模型研究将为代谢信号通路的调节和功能提供新的见解。进一步的研究可能导致确定新的治疗目标，并最终帮助开发针对肥胖症和糖尿病的合理的、基于机制的治疗策略。