It is well known in humans that Parkinson's disease results from the specific degeneration of dopaminergic neurons in the pars compacta of the substantia nigra of the mesencephalon. The relatively new strategy of neuronal transplantation has provided encouraging results for Parkinson's disease patients, but unfortunately the survival of dopaminergic neurons in these transplants is extremely poor. We propose to increase neuronal survival in neural transplants by focal stimulation of angiogenesis. Using a replication-deficient herpes simplex viral vector containing the cDNA for human vascular endothelial growth factor(VEGF), we propose to increase expression of VEGF in dopaminergic cultures of embryonic rat mesencephalon, and examine whether steriotactic transplantation of these cells into adult rat striatum increases parameters of angiogenesis and neuronal survival within the transplant, such as blood vessel number, total cell number and the number of tyrosine hydroxylase-immunoreactive cells. Using a chemically lesioned rat model which creates a specific dopaminergic deficit similar to that seen in Parkinson's disease, we will test the efficacy and long term survival of these transplants using behavioral tests such as drug-induced stereotypic rotations. The implications of these results could have an immediate impact on current clinical transplantation strategies for Parkinson's disease, and furthermore have general implications for improving cell survival in other neural transplantation paradigms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS036826-02S2
Application #
6467511
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Heemskerk, Jill E
Project Start
1999-07-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$44,990
Indirect Cost
Name
Montefiore Medical Center (Bronx, NY)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10467
Casper, Diana; Finkelstein, Eric; Goldstein, Ira M et al. (2003) Dopaminergic neurons associate with blood vessels in neural transplants. Exp Neurol 184:785-93
Casper, Diana; Engstrom, Samara J; Mirchandani, Gautam R et al. (2002) Enhanced vascularization and survival of neural transplants with ex vivo angiogenic gene transfer. Cell Transplant 11:331-49
Casper, D; Yaparpalvi, U; Rempel, N et al. (2000) Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro. Neurosci Lett 289:201-4