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: 8359744
• 负责人: Paige C Geiger
• 金额: $ 12.1万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359744
• 关键词: Antioxidants; Biomedical Research; Chronic stress; Data; Development; Disease; Fatty acid glycerol esters; Funding; Glycogen Synthase Kinase 3; Goals; Grant; Heat shock proteins; Insulin Resistance; Insulin Signaling Pathway; JUN gene; Kansas; Lead; Molecular; Muscle; National Center for Research Resources; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Phosphotransferases; Predisposition; Prevention; Principal Investigator; Property; Research; Research Infrastructure; Resources; Role; Signal Pathway; Skeletal Muscle; Source; Stress; Testing; United States National Institutes of Health; Wistar Rats; combat; cost; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

这个子项目是利用这些资源的众多研究子项目之一