PD is a progressive neurodegenerative disorder of unknown etiology that results in the loss of dopamine neurons projecting from substantia nigra to striatum. My colleagues and I have shown that if a cast is placed on the ipsilateral limb during the first 7 days prior to or following unilateral 6-OHDA infusion, forcing reliance on the impaired contralateral limb, both the behavioral and neurochemical deficits are reduced (Tillerson et al, 2001; 2002; Cohen et al, 2003). The mechanism underlying the protective effect of forced limb use is unknown. However I have shown that GDNF, a potent dopaminotrophic factor that protects against 6-OHDA toxicity (e.g., Kearns and Gash, 1995; Choi-Lundberg et al, 1998), is increased with forced limb use, indicating that it may be involved in the protective effects of forced limb use against 6-OHDA (Cohen et al, 2003). Although the mechanism by which GDNF might exert its protective effects is also unknown, evidence suggests that GDNF acts in part through the Ras/ERK signaling cascade (eg: Soler et al., 1999).
The specific aims for this project are:
Aim 1 : Determine the impact of prior forced limb use on the anatomical state of DA neurons after 6-OHDA.
Aim 2 : Determine if the ERK signaling cascade is involved in forced-limb use-induced increases in GDNF and resulting neuroprotection.
Aim 3 : Determine the relationship between increases in GDNF in the striatum and the neuroprotective effects of forced limb use.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS047831-01A1
Application #
6885096
Study Section
Special Emphasis Panel (ZRG1-F01 (20))
Program Officer
Refolo, Lorenzo
Project Start
2005-01-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
1
Fiscal Year
2005
Total Cost
$43,593
Indirect Cost
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213