Projects and Grants per year
Grants and Contracts Details
Description
The neurorestorative and neuroprotective trophic actions of GDNF on midbrain dopamine (DA) neurons
provide a promising but controversial therapeutic approach for the treatment of Parkinson's disease. We
specifically plan to address the following major issues in the next 5 years of support for the University of
Kentucky Udall Center: 1) We hypothesize that GDNF is affecting DA neurons through at least 3 major
mechanisms: A) Upregulation of existing DA neurons - direct effects on tyrosine hydroxylase and related
proteins (Project 1); B) Repair of DA neurons and connections - improved dendritic and neuronal fiber
connections (Projects 2 and 3); and C) Neurogenesis and/or gliogenesis (Project 3). We will investigate
these three mechanisms in the proposed experiments in nonhuman primate models of PD. 2) We propose to
use a novel indwelling pump that can deliver GDNF chronically in the freely-moving MPTP-Iesioned monkey
to evaluate multisite delivery of GDNF (putamen vs. putamen + substantia nigra) to improve the functional
restoration of DA systems. 3) Recent studies in PD patients involving a Phase 2 clinical trial have yielded
controversial data regarding potential GDNF antibody formation and preliminary toxicology studies in rhesus
monkeys support a potential toxicity of GDNF to cerebellar Purkinje cells and granule cells, when chronically
administered in high doses (100 I-Ig/day) and subsequently withdrawn. In conjunction with Projects 2 and 3,
we will investigate the potential toxic effects of GDNF on dopamine and non-dopamine containing cells in the
CNS. In addition, we will investigate potential antibody formation from chronic GDNF administration. 4)
Finally, we will use an improved delivery approach, to investigate the effects of GDNF infusion on milder
parkinsonism in unilateral MPTP-treated monkeys, to investigate if earlier intervention of GDNF treatment
may contribute to better functional recovery of the nigrostriatal system. We will utilize a recently developed
stable, unilateral milder parkinsonian monkey model for these studies, which may be an "earlystage"
model of PD. The different highly integrated Projects and Cores will provide key data
regarding the functional effects of chronic GDNF treatments to DA neurons, mechanisms of action of
GDNF both positive and negative, and will provide data that may be useful to gain a better
understanding of the effects of trophic factors on dead or dying neurons.
Status | Finished |
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Effective start/end date | 9/30/99 → 7/31/07 |
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Projects
- 1 Finished
-
Morris K. Udall Parkinson's Center of Excellence: Restoration of Dopaminergic Function in Parkinson's Disease
Gerhardt, G., ANDERSON, A., Gash, D., Grondin, R., Hardy, P., Kaplan, A., Kryscio, R., Markesbery, W. & Zhang, Z.
National Institute of Neurological Disorders & Stroke
9/30/99 → 7/31/07
Project: Research project