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: 8278565
• 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/8278565
• 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，并建立预防胰岛素抵抗的新型HSP疗法。长期目标是阐明肌肉胰岛素抵抗的机制，导致2型糖尿病患病率随年龄增长而增加。该特定应用的目的是确定增加的HSP表达可以调节骨骼肌中的应激激酶和胰岛素信号传导途径的程度。我们的中心假设是，增加HSP 72和HSP 25的表达将减少应激激酶的激活，并改善胰岛素信号。我们提出这项研究的理由是，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测试：1）确定HSP依赖性机制，其功能是改善骨骼肌胰岛素信号传导; 2）确定调节胰岛素抵抗骨骼肌中HSP表达的信号传导途径; 3）确定治疗干预措施，以改善老年骨骼肌中HSP活化和胰岛素信号传导。在特定目标1中，我们将确定HSP 72和HSP 25表达的增加是否分别抑制应激激酶c-jun末端激酶（JNK）和κ B激酶2（IKK 2）抑制剂，并改善年轻（6和12月龄）和老年（18和24月龄）Fischer 344大鼠的胰岛素信号传导。我们将使用热处理和通过质粒转染的热休克蛋白的特异性过表达来实现这一目标。在具体目标2中，我们将确定糖原合成酶激酶-3（GSK-3）和JNK信号通路在多大程度上调节胰岛素抵抗骨骼肌中HSP的表达。GSK-3和JNK的药理学抑制剂将用于修饰主要HSP转录因子热休克因子1（HSF-1）的活化。在具体目标3中，我们将研究运动训练增加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年胰岛素抵抗骨骼肌中胰岛素信号传导和葡萄糖摄取的附加改善。作为所提出的目标的一个结果，我们期望建立一个新的治疗作用，热休克蛋白在对抗胰岛素抵抗和确定的分子机制，调节HSP表达的老年人，胰岛素抵抗的骨骼肌。这个项目是创新的，因为它旨在确定一个以前未探索的机制，通过增加骨骼肌中热休克蛋白的表达来改善胰岛素抵抗。这项研究意义重大，因为它将有助于建立预防胰岛素抵抗的重要新候选靶点，并增强我们对随着年龄和疾病发生的细胞防御能力下降的理解。 公共卫生相关性：在完成这些研究，我们希望增加我们的理解的基本抗氧化特性的热休克蛋白在骨骼肌和确定的热休克蛋白依赖性机制的保护作用的热处理胰岛素的行动。这样的结果将对公共卫生产生重要的积极影响，因为它确定了治疗干预的新目标，这将有助于美国越来越多的老年人患上胰岛素抵抗和2型糖尿病。