Targeting stress-mediated pathways in the treatment of muscle insulin resistance

靶向应激介导的途径治疗肌肉胰岛素抵抗

• 批准号: 8121383
• 负责人: Paige C Geiger
• 金额: $ 23.65万
• 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: 2010-08-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121383
• 关键词: Acceleration; Address; Affect; Age; Aging; Antioxidants; Apoptotic; Biogenesis; Chronic; Clinical Data; Cytoprotection; Data; Development; Diabetes Mellitus; Diet; Disease; Elderly; Environment; Exercise; Gene Expression; Glucose Intolerance; Glycogen Synthase Kinase 3; Goals; HSP72 protein; Heat Stress Disorders; Heat shock proteins; Heating; Hyperinsulinism; In Vitro; Inflammation Mediators; Institutes; Insulin; Insulin Resistance; Insulin Signaling Pathway; JUN gene; Laboratories; Laboratory Research; Lead; Literature; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Pathway interactions; Patients; Pattern; Persons; Phosphorylation; Phosphotransferases; Plasmids; Prevalence; Prevention; Preventive Intervention; Property; Protein Family; Public Health; Publishing; Rattus; Regulation; Research; Risk; Role; Serine; Signal Pathway; Signal Transduction; Skeletal Muscle; Stress; System; Testing; Therapeutic; Therapeutic Intervention; Training; Transfection; Up-Regulation; Work; age related; aged; base; biological adaptation to stress; combat; design; experience; glucose uptake; heat-shock factor 1; improved; inhibitor/antagonist; innovation; insulin receptor substrate 1 protein; insulin sensitivity; insulin signaling; kinase inhibitor; muscle aging; muscle metabolism; novel; novel therapeutics; overexpression; prevent; protective effect; protein activation; protein expression; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): 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. The long-term goal is to elucidate the mechanisms of muscle insulin resistance that lead to increased prevalence of type 2 diabetes with advancing age. 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. Our rationale for the proposed research is that new strategies could be developed to modulate HSP-dependent pathways as a therapeutic approach to treat insulin resistance. Guided by strong preliminary data, this hypothesis will be tested by pursuing three 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; and 3) Identify therapeutic interventions to improve HSP activation and insulin signaling in aged 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 2 (IKK2), respectively, and improve insulin signaling in young (6- and 12-month-old) and aged (18- and 24-month-old) Fischer 344 rats. We will use both heat treatment and specific overexpression of HSPs via plasmid transfection to accomplish this aim. 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. Pharmacolgocial inhibitors of GSK-3 and JNK will be used to modify activation of the primary HSP transcription factor, heat shock factor 1 (HSF-1). In Specific Aim 3, we will examine the ability of exercise training to increase the HSP response in young and aged, insulin-resistant skeletal muscle. Our working hypothesis is that exercise training will trigger the HSP response through a pathway independent of heat treatment, and that heat stress and exercise will result in an additive improvement of insulin signaling and glucose uptake in aged, insulin-resistant skeletal muscle. 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 aged, insulin-resistant skeletal muscle. This project is innovative, because it is designed to identify a previously unexplored mechanism for improving insulin resistance via increased expression of HSPs in 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 age and disease. PUBLIC HEALTH RELEVANCE: At the completion of these studies, we expect to increase our understanding of the fundamental antioxidant properties of heat shock proteins in skeletal muscle and to identify the heat shock protein-dependent mechanisms underlying the protective effect of heat treatment on insulin action. Such results would have an important positive impact on public health by identifying new targets for therapeutic interventions that will aid the growing number of elderly persons in the U.S. at risk for developing insulin resistance and type 2 diabetes.

描述（由申请人提供）：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。长期目标是阐明肌肉胰岛素抵抗的机制，该机制导致 2 型糖尿病患病率随着年龄的增长而增加。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。我们提出的研究的理由是，可以开发新的策略来调节 HSP 依赖性途径，作为治疗胰岛素抵抗的治疗方法。在强有力的初步数据的指导下，这一假设将通过追求三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； 3) 确定治疗干预措施，以改善老化骨骼肌中的 HSP 激活和胰岛素信号传导。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 2 抑制剂 (IKK2)，并改善年轻人（6 岁和 6 岁以下）的胰岛素信号传导。 12 个月大）和老年（18 个月和 24 个月大）Fischer 344 大鼠。我们将通过质粒转染使用热处理和 HSP 特异性过表达来实现这一目标。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改变主要 HSP 转录因子、热休克因子 1 (HSF-1) 的激活。在具体目标 3 中，我们将检查运动训练提高年轻和老年胰岛素抵抗骨骼肌 HSP 反应的能力。我们的工作假设是，运动训练将通过独立于热处理的途径触发 HSP 反应，并且热应激和运动将导致老化的胰岛素抵抗骨骼肌中胰岛素信号和葡萄糖摄取的额外改善。作为所提出目标的结果，我们期望在对抗胰岛素抵抗方面建立 HSP 的新治疗作用，并确定调节老化、胰岛素抵抗骨骼肌中 HSP 表达的分子机制。该项目具有创新性，因为它旨在确定一种以前未探索过的机制，通过增加骨骼肌中 HSP 的表达来改善胰岛素抵抗。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靶点，并增强我们对随年龄和疾病而发生的细胞防御能力下降的理解。 公共健康相关性：完成这些研究后，我们希望加深对骨骼肌中热休克蛋白基本抗氧化特性的了解，并确定热处理对胰岛素作用保护作用背后的热休克蛋白依赖性机制。这些结果将确定新的治疗干预目标，从而对公共健康产生重要的积极影响，从而帮助美国越来越多面临胰岛素抵抗和 2 型糖尿病风险的老年人。