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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR016475-11
Application #
8359744
Study Section
Special Emphasis Panel (ZRR1-RI-4 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
11
Fiscal Year
2011
Total Cost
$121,001
Indirect Cost
Name
University of Kansas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Pang, Xiao-Yan; Wang, Suya; Jurczak, Michael J et al. (2017) Retinol saturase modulates lipid metabolism and the production of reactive oxygen species. Arch Biochem Biophys 633:93-102
Barton, Janice S; Schomacker, Rachel (2017) Comparative protein profiles of the Ambrosia plants. Biochim Biophys Acta 1865:633-639
Dowdell, Alexander S; Murphy, Maxwell D; Azodi, Christina et al. (2017) Comprehensive Spatial Analysis of the Borrelia burgdorferi Lipoproteome Reveals a Compartmentalization Bias toward the Bacterial Surface. J Bacteriol 199:
Chakrabarti, Rima S; Ingham, Sally A; Kozlitina, Julia et al. (2017) Variability of cholesterol accessibility in human red blood cells measured using a bacterial cholesterol-binding toxin. Elife 6:
Bowden, John A; Heckert, Alan; Ulmer, Candice Z et al. (2017) Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma. J Lipid Res 58:2275-2288
Guilford, B L; Ryals, J M; Lezi, E et al. (2017) Dorsal Root Ganglia Mitochondrial Biochemical Changes in Non-diabetic and Streptozotocin-Induced Diabetic Mice Fed with a Standard or High-Fat Diet. J Neurol Neurosci 8:
Rogers, Robert S; Tungtur, Sudheer; Tanaka, Tomohiro et al. (2017) Impaired Mitophagy Plays a Role in Denervation of Neuromuscular Junctions in ALS Mice. Front Neurosci 11:473
Moon, Sanghee; Schmidt, Marshall; Smirnova, Irina V et al. (2017) Qigong Exercise May Reduce Serum TNF-? Levels and Improve Sleep in People with Parkinson's Disease: A Pilot Study. Medicines (Basel) 4:
Pook, Victoria G; Nair, Meera; Ryu, KookHui et al. (2017) Positioning of the SCRAMBLED receptor requires UDP-Glc:sterol glucosyltransferase 80B1 in Arabidopsis roots. Sci Rep 7:5714
Kania-Korwel, Izabela; Wu, Xianai; Wang, Kai et al. (2017) Identification of lipidomic markers of chronic 3,3',4,4',5-pentachlorobiphenyl (PCB 126) exposure in the male rat liver. Toxicology 390:124-134

Showing the most recent 10 out of 639 publications