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: 8469372
• 负责人: Paige C Geiger
• 金额: $ 22.35万
• 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/8469372
• 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.

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疗法以防止胰岛素抵抗。长期目标是阐明肌肉胰岛素抵抗的机制，导致随着年龄的增长，导致2型糖尿病的患病率增加。该特定应用的目的是确定增加HSP表达可以在骨骼肌中调节应力激酶和胰岛素信号通路的程度。我们的中心假设是，HSP72和HSP25的表达增加将降低应力激酶激活并改善胰岛素信号传导。我们对拟议的研究的理由是，可以开发出新的策略来调节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，将通过追求三个特定目的来检验该假设：1）确定依赖HSP的机制，这些机制可以改善骨骼肌肉胰岛素信号传导； 2）确定在抗胰岛素抗骨骼肌中调节HSP表达的信号传导途径； 3）确定治疗性干预措施，以改善老年骨骼肌的HSP激活和胰岛素信号传导。在特定目标1中，我们将确定HSP72和HSP25的表达增加是否抑制了应激激酶C-JUN末端激酶（JNK）和Kappa B激酶2（IKK2）的抑制剂（IKK2），并改善年轻（6-和12个月大的）（18-和12个月大）的（18-和12个月大）和24-Month-Month-Month-fist的年轻胰岛素信号。我们将通过质粒转染使用热处理和HSP的特异性过表达来实现这一目标。在特定的目标2中，我们将确定糖原合酶激酶3（GSK-3）和JNK信号通路在胰岛素耐药骨骼肌中调节HSP表达的程度。 GSK-3和JNK的药物凝聚抑制剂将用于修饰原发性HSP转录因子的激活，热休克因子1（HSF-1）。在特定的目标3中，我们将研究运动训练增加年轻和年龄耐胰岛素骨骼肌的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胰岛素信号传导和耐胰岛素耐药骨骼肌的胰岛素信号传导和葡萄糖摄取的累加改善。作为所提出的目标的结果，我们希望建立HSP在打击胰岛素抵抗和鉴定调节型老年胰岛素耐药骨骼肌中HSP表达的分子机制方面的新型治疗作用。该项目具有创新性，因为它旨在通过增加骨骼肌中HSP的表达来确定以前未开发的机制来改善胰岛素抵抗。拟议的研究很重要，因为它将有助于建立重要的新候选靶标，以预防胰岛素抵抗，并增强我们对随着年龄和疾病的细胞防御能力下降的理解。