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.
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