Neurotrophic factors (neurotrophins, GDNF and CNTF) can rescue injured dopaminergic neurons of the substantia nigra in adult rodent models of Parkinson's disease by activating transmembrane tyrosine kinase receptors or associated tyrosine kinases. Signaling is terminated by protein tyrosine phosphatases (PTPs), which have a high degree of specificity and are critical for cellular processes, including neural development. A major problem with large neurotrophic factors proteins is their poor ability to reach the brain regions of interest. We have shown that a small general PTP inhibitor can protect injured dopaminergic neurons in rats and dramatically increase the protective effects of a neurotrophin BDNF, suggesting that TrkB signaling was enhanced. Little is known about the identity of PTPs involved in regulating neuronal survival-related signaling. We will use a functional proteomics approach by co-immunoprecipitation techniques to isolate the specific PTPs that associate with the neurotrophic receptors after neurotrophic factor stimulation in rats, mice and cultured neuronal cells. The identification of such important PTPs will provide a basis for assessing their normal and pathophysiological roles and a platform to develop more selective inhibitors for future clinical use.
A second aim i s to evaluate whether the PTP inhibitor can also enhance protective effects of GDNF or CNTF in an animal model of Parkinson's disease. This could generalize the idea of PTP inhibition as a therapeutic approach, and will be useful for predicting which of the PTPs, identified in the first aim, are affected by the PTP inhibitor. These studies will increase our understanding of how dopaminergic neurons function, validate our new treatment approach and provide us with research tools to improve it for application to Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS044706-01
Application #
6552853
Study Section
Special Emphasis Panel (ZNS1-SRB-K (03))
Program Officer
Oliver, Eugene J
Project Start
2002-06-01
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
1
Fiscal Year
2002
Total Cost
$178,750
Indirect Cost
Name
University of Louisville
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40292