Abstract

Recent findings suggest that apoptosis or programmed cell death contributes to diabetic neuropathy, and, moreover, treatment with IGF-1 protects nerves by inhibiting glucose-induced apoptosis, apparently by signaling through the IGF-1 receptor, phosphatidylinositol 3-kinase (PI3K) and Akt. Akt in turn appears to phosphorylate and inhibit BAD, thereby interrupting an otherwise constitutive interaction of BAD with Bcl-xL, thereby freeing up Bcl-xL, which maintains mitochondrial integrity and prevents apoptosis. The present proposal will test this hypothesis in neural cells in three ways: (1) determine the role of IGF-I receptor-dependent signaling cascades in IGF-1 mediated neuroprotection; (2) examine the function of BAD phosphorylation and BAD/Bcl-xL association in IGF-mediated neuroprotection; and (3) characterize neuronal apoptosis and clinical endpoints of diabetic neuropathy in streptozotocin-diabetic rats treated with IGF-1. The ultimate goal is to understand the pathogenesis of diabetic neuropathy, and develop new treatment strategies for this problem.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038849-02
Application #
2892486
Study Section
Special Emphasis Panel (ZRG2-NMS (01))
Program Officer
Nichols, Paul L
Project Start
1998-09-30
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Zilliox, L; Peltier, A C; Wren, P A et al. (2011) Assessing autonomic dysfunction in early diabetic neuropathy: the Survey of Autonomic Symptoms. Neurology 76:1099-105
Lentz, Stephen I; Edwards, James L; Backus, Carey et al. (2010) Mitochondrial DNA (mtDNA) biogenesis: visualization and duel incorporation of BrdU and EdU into newly synthesized mtDNA in vitro. J Histochem Cytochem 58:207-18
Haines, Kristine M; Feldman, Eva L; Lentz, Stephen I (2010) Visualization of mitochondrial DNA replication in individual cells by EdU signal amplification. J Vis Exp :
Kim, Bhumsoo; Feldman, Eva L (2009) Insulin receptor substrate (IRS)-2, not IRS-1, protects human neuroblastoma cells against apoptosis. Apoptosis 14:665-73
Sadidi, Mahdieh; Lentz, Stephen I; Feldman, Eva L (2009) Hydrogen peroxide-induced Akt phosphorylation regulates Bax activation. Biochimie 91:577-85
Vincent, Andrea M; Kato, Koichi; McLean, Lisa L et al. (2009) Sensory neurons and schwann cells respond to oxidative stress by increasing antioxidant defense mechanisms. Antioxid Redox Signal 11:425-38
Peltier, Amanda; Smith, A Gordon; Russell, James W et al. (2009) Reliability of quantitative sudomotor axon reflex testing and quantitative sensory testing in neuropathy of impaired glucose regulation. Muscle Nerve 39:529-35
Dowling, James J; Vreede, Andrew P; Kim, Susie et al. (2008) Kindlin-2 is required for myocyte elongation and is essential for myogenesis. BMC Cell Biol 9:36
Dowling, James J; Gibbs, Elizabeth M; Feldman, Eva L (2008) Membrane traffic and muscle: lessons from human disease. Traffic 9:1035-43
Sullivan, Kelli A; Lentz, Stephen I; Roberts Jr, John L et al. (2008) Criteria for creating and assessing mouse models of diabetic neuropathy. Curr Drug Targets 9:3-13

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