The most common complication of diabetes is neuropathy, which occurs, in approximately 60 percent of all diabetic patients. Our work has generated a new theory: that glucose-mediated apoptosis contributes to the development of diabetic neuropathy and that interrupting the death pathway with insulin-like growth factor-I (IGF-I) could afford a new means of therapy. This application aims to understand how glucose kills and IGF-I rescues neurons in both cell culture and animal models of diabetic neuropathy. We speculate high glucose promotes the formation of reactive oxygen species (ROS). Mt membrane depolarization (MMD) then occurs in direct response to glucose, ROS or dimerization of the anti-apoptotic protein Bcl-xL with the pro-apoptotic proteins Bax/Bak. In each case, there is release of Mt cytochrome c into the cytosol and activation of the caspase cascade. It is unknown if caspases can be directly cleaved by ROS, or which initiator (-8 or -9) or downstream effector (-3 through -7) caspases are involved in the cascade. IGF-I may interrupt cell death at one or more points in the pathway. Human neuroblastoma cells, primary sensory neurons and mouse models are used to test this model. We have 4 aims: 1. Characterize ROS formation and the point of IGF-I protection following glucose exposure 2. Characterize the roles of Bcl proteins and determine the point of IGF-I protection following glucose exposure 3. Characterize the caspase cascade and determine the point of IGF-I protection following glucose exposure 4. Use genetically altered mice to characterize the death pathway in clinical diabetic neuropathy and determine the point of IGF-I protection

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038849-05
Application #
6766835
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Porter, John D
Project Start
1998-09-30
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
5
Fiscal Year
2004
Total Cost
$213,437
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
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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
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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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