Diabetic peripheral neuropathy (DPN) is a common complication in diabetic individuals that results from a progressive degeneration of neurons and Schwann cells (SCs). Although much attention has focused on neuronal loss in DPN, SCs also undergo substantial degeneration and are critical for re-establishing axon- glial interaction necessary for regeneration. Analysis of the inter-related metabolic insults induced by hyper- glycemia have identified that increased production of superoxide anion may be a focal event that contributes to mitochondria! dysfunction and apoptosis of SCs. On the other hand, insulin-like growth factor-1 (IGF-1) decreases mitochondrial dysfunction and apoptosis of SCs. To date, the role of oxidative stress and IGF-1 in regulating mitochondrial function in SCs have focused only on a small subset of proteins that contribute to apoptosis. However, it is unclear that SCs undergo extensive apoptosis in DPN. We hypothesize that the opposing effects of superoxide production and IGF-1 signaling in SCs may be more critical in balancing changes in both the expression and post-translational modification of mitochondrial proteins that affect aspects of organellar homeostasis central to regulating SC regeneration. Since a significant gap exists with regard to the broad effect of glucose-induced superoxide production and IGF-1 signaling in maintaining the mitochondrial proteome, our specific aims are to: 1) Identify the role of glucose-induced superoxide production in altering the mitochondrial proteome of SCs using pharmacological, molecular and quantitative proteomic approaches. 2) Identify the role of glucose-induced superoxide production in enhancing the level of tyrosine nitration in the mitochondrial proteome. 3) Identify the sufficiency/necessity of phosphatidyl- inositol 3 kinase in attenuating glucose-induced superoxide production by IGF-1. Collectively, our studies will identify mitochondrial proteins that are susceptible to glucose-induced oxidative stress and improve our understanding of how growth factor signaling may improve mitochondrial function in diabetic nerve.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073594-03
Application #
7332211
Study Section
Special Emphasis Panel (ZDK1-GRB-N (O1))
Program Officer
Jones, Teresa L Z
Project Start
2006-01-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
3
Fiscal Year
2008
Total Cost
$369,204
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Kusuma, Bhaskar Reddy; Zhang, Liang; Sundstrom, Teather et al. (2012) Synthesis and evaluation of novologues as C-terminal Hsp90 inhibitors with cytoprotective activity against sensory neuron glucotoxicity. J Med Chem 55:5797-812
Zhang, Liang; Zhao, Huiping; Blagg, Brian S J et al. (2012) C-terminal heat shock protein 90 inhibitor decreases hyperglycemia-induced oxidative stress and improves mitochondrial bioenergetics in sensory neurons. J Proteome Res 11:2581-93
Chowdhury, Subir K Roy; Dobrowsky, Rick T; Fernyhough, Paul (2011) Nutrient excess and altered mitochondrial proteome and function contribute to neurodegeneration in diabetes. Mitochondrion 11:845-54
Akude, Eli; Zherebitskaya, Elena; Chowdhury, Subir K Roy et al. (2011) Diminished superoxide generation is associated with respiratory chain dysfunction and changes in the mitochondrial proteome of sensory neurons from diabetic rats. Diabetes 60:288-97
Haenchen, Steve D; Utter, Jeff A; Bayless, Adam M et al. (2010) Role of a cdk5-associated protein, p35, in herpes simplex virus type 1 replication in vivo. J Neurovirol 16:405-9
Urban, Michael J; Li, Chengyuan; Yu, Cuijuan et al. (2010) Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice. ASN Neuro 2:e00040
Oien, Derek B; Ortiz, Andrea N; Rittel, Alexander G et al. (2010) Dopamine D(2) receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse. J Neurochem 114:51-61
Sharov, Victor S; Dremina, Elena S; Galeva, Nadezhda A et al. (2010) Fluorogenic Tagging of Peptide and Protein 3-Nitrotyrosine with 4-(Aminomethyl)-benzenesulfonic Acid for Quantitative Analysis of Protein Tyrosine Nitration. Chromatographia 71:37-53
Zhang, Liang; Yu, Cuijuan; Vasquez, Francisco E et al. (2010) Hyperglycemia alters the schwann cell mitochondrial proteome and decreases coupled respiration in the absence of superoxide production. J Proteome Res 9:458-71
McGuire, James F; Rouen, Shefali; Siegfreid, Eric et al. (2009) Caveolin-1 and altered neuregulin signaling contribute to the pathophysiological progression of diabetic peripheral neuropathy. Diabetes 58:2677-86

Showing the most recent 10 out of 11 publications