PROTECTIVE ROLE OF HEAT SHOCK PROTEINS IN INSULIN RESISTANCE

热休克蛋白在胰岛素抵抗中的保护作用

• 批准号: 8167524
• 负责人: Paige C Geiger
• 金额: $ 12.14万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167524
• 关键词: Antioxidants; Chronic stress; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Disease; Fatty acid glycerol esters; Funding; Glycogen Synthase Kinase 3; Goals; Grant; Heat shock proteins; Institution; Insulin Resistance; Insulin Signaling Pathway; JUN gene; Lead; Molecular; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Phosphotransferases; Predisposition; Prevention; Property; Research; Research Personnel; Resources; Role; Signal Pathway; Skeletal Muscle; Source; Stress; Testing; United States National Institutes of Health; Wistar Rats; combat; feeding; heat-shock factor 1; improved; inhibitor/antagonist; insulin signaling; kinase inhibitor; novel; novel therapeutics; prevent; protein expression; transcription factor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is a critical need to understand the fundamental antioxidant properties of heat shock proteins (HSPs) in skeletal muscle and establish novel HSP therapies for preventing insulin resistance. Our long-term goal is to elucidate the mechanisms of muscle insulin resistance that lead to the development of type 2 diabetes. The objective of this particular application is to determine the extent to which increased HSP expression can modulate stress kinase and insulin signaling pathways in skeletal muscle. Our central hypothesis is that increased expression of HSP72 and HSP25 will decrease stress kinase activation and improve insulin signaling. We further hypothesize that chronic stress kinase activation results in low HSP expression in high fat-fed insulin-resistant skeletal muscle, increasing susceptibility to oxidative stress. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify HSP-dependent mechanisms that function to improve skeletal muscle insulin signaling; 2) Identify signaling pathways that modulate HSP expression in insulin-resistant skeletal muscle. In Specific Aim 1, we will determine whether increased expression of HSP72 and HSP25 inhibit the stress kinases c-jun terminal kinase (JNK) and inhibitor of kappa B kinase beta.(IKKbeta), respectively, and improve insulin signaling in chow-fed and high fat-fed, insulin resistant Wistar rats. In Specific Aim 2, we will determine the extent to which glycogen synthase kinase-3 (GSK-3) and JNK signaling pathways modulate HSP expression in insulin-resistant skeletal muscle. Pharmacological inhibitors of GSK-3 and JNK will be used to potentially modify activation of the primary HSP transcription factor, heat shock factor 1 (HSF-1). As an outcome of the proposed aims, we expect to establish a novel therapeutic role for HSPs in combating insulin resistance and identify molecular mechanisms that regulate HSP expression in insulin-resistant skeletal muscle. The proposed research is significant because it will help to establish important new candidate targets for prevention of insulin resistance as well as enhance our understanding of the decline in cellular defenses that occurs with numerous disease states.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 迫切需要了解骨骼肌中热休克蛋白 (HSP) 的基本抗氧化特性，并建立新的 HSP 疗法来预防胰岛素抵抗。我们的长期目标是阐明导致 2 型糖尿病发展的肌肉胰岛素抵抗机制。 这一特定应用的目的是确定增加的 HSP 表达可以在多大程度上调节骨骼肌中的应激激酶和胰岛素信号传导途径。我们的中心假设是 HSP72 和 HSP25 表达的增加将减少应激激酶激活并改善胰岛素信号传导。我们进一步假设慢性应激激酶激活导致高脂肪喂养的胰岛素抵抗骨骼肌中 HSP 表达低，从而增加对氧化应激的敏感性。在强有力的初步数据的指导下，这一假设将通过追求两个具体目标进行检验：1）确定能够改善骨骼肌胰岛素信号传导的 HSP 依赖性机制； 2) 确定调节胰岛素抵抗骨骼肌中 HSP 表达的信号通路。在具体目标 1 中，我们将确定 HSP72 和 HSP25 表达的增加是否分别抑制应激激酶 c-jun 末端激酶 (JNK) 和 kappa B 激酶 β 抑制剂 (IKKbeta)，并改善饲料喂养和高脂肪喂养、胰岛素抵抗的 Wistar 大鼠。在具体目标 2 中，我们将确定糖原合酶激酶 3 (GSK-3) 和 JNK 信号通路调节胰岛素抵抗骨骼肌中 HSP 表达的程度。 GSK-3 和 JNK 的药理学抑制剂将用于潜在地改变主要 HSP 转录因子热休克因子 1 (HSF-1) 的激活。作为所提出目标的结果，我们期望建立 HSP 在对抗胰岛素抵抗方面的新治疗作用，并确定调节胰岛素抵抗骨骼肌中 HSP 表达的分子机制。拟议的研究意义重大，因为它将有助于建立预防胰岛素抵抗的重要新候选目标，并增强我们对多种疾病状态下发生的细胞防御能力下降的理解。