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（由申请人提供）：肥胖和糖尿病等慢性代谢疾病的发生率显着增加，构成了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）的发病机理中起着至关重要的作用。氧化应激和内质网（ER）应激会促进细胞功能障碍，凋亡和胰岛素抵抗。尽管细胞应激的激活剂和下游效应已部分表征，但在调节细胞应激反应的分子机制方面，尚不清楚。我们的实验室和其他实验室最近表征了NLR（NBD-LRR）蛋白质家族，这些家族已被证明可以介导细胞应激对微生物和环境应激源的反应。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（MROS）的产生来促进ER应力反应。从机械上讲，NLRX1与ECSIT（进化保守的信号传导中间体）和TRAF6（TNF受体相关因子6）直接关联，它们在线粒体呼吸链组件中都很重要。 NLRX1缺陷型（NLRX1 - / - ）细胞受到侵害ER抑制胰岛素PI3K-AKT途径的保护。此外，通过高脂饮食（HFD）喂养保护NLRX1 - / - 小鼠免受肥胖诱导的胰岛素抵抗。因此，我假设NLRX1通过促进ECSIT-TRAF6功能来介导MROS的产生，后者随后促进ER应激，并且NLRX1介导的细胞胁迫反应会损害胰岛素靶组织中的胰岛素胰岛素信号传导。我将采用T2D（HFD进食和缺乏瘦素的OB/OB小鼠）动物模型来检查NLRX1介导的细胞应激反应在胰岛素抵抗中的功能。我将研究NLRX1如何控制ECSIT功能和MROS产生。该提案的目的是检查NLRX1介导的氧化应激与ER应激之间相互作用的机制，以促进细胞功能障碍和胰岛素信号传导的缺陷。提出的遗传和生化分析和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鉴定新的治疗靶标，并最终有助于制定靶向肥胖和糖尿病的理性，基于机制的治疗策略。