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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS043023-03
Application #
6693362
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Porter, John D
Project Start
2002-01-01
Project End
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
3
Fiscal Year
2004
Total Cost
$29,987
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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