The goal of this application is to determine the molecular mechanism underlying diabetic neuropathy in dorsal root ganglion (DRG) neurons. Our hypothesis is that neurons exposed to high glucose undergo apoptosis via activation of apoptosis signal-regulated kinase 1 (ASKI), which activates the c-Jun N-terminal kinase (JNK) pathway. Insulin-like growth factor I (IGF-I) is predicted to protect DRG from glucose-mediated apoptosis by blocking activation of a component of the JNK pathway. This application will analyze glucose-treated DRG by TUNEL analysis and western blotting to determine 1) apoptotic molecules induced by JNK activation, 2) the role of ASKI on JNK activation and apoptosis and 3) the effect of IGF-I on JNK pathway activation and apoptotic regulatory proteins. At the conclusion of these studies we will understand how the JNK pathway functions in a model of diabetic neuropathy and how IGF-I mediates neuroprotection. These findings will advance our understanding of neuronal injury and may suggest potential therapeutic interventions for treatment of diabetic neuropathy.
| Leinninger, Gina M; Backus, Carey; Sastry, Ann Marie et al. (2006) Mitochondria in DRG neurons undergo hyperglycemic mediated injury through Bim, Bax and the fission protein Drp1. Neurobiol Dis 23:11-22 |
| Leinninger, Gina M; Feldman, Eva L (2005) Insulin-like growth factors in the treatment of neurological disease. Endocr Dev 9:135-59 |
| Leinninger, Gina M; Vincent, Andrea M; Feldman, Eva L (2004) The role of growth factors in diabetic peripheral neuropathy. J Peripher Nerv Syst 9:26-53 |
| Leinninger, Gina M; Backus, Carey; Uhler, Michael D et al. (2004) Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons. FASEB J 18:1544-6 |
