The long-term objective of this proposal is to establish clonal lines of dopamine (DA)-producing nerve cells in vitro in order to evaluate their efficacy in improving the symptoms of Parkinson's disease (PD). We have established clonal lines of rat immortalized DA-producing nerve cells in vitro and can generate 100 percent terminally differentiated neuroblastoma (NB) cells. The immortalized cells when transplanted into the striatum of rats with 6- hydroxydopamine (6-OHDA) lesions, survived, did not produce tumors and reduced amphetamine-induced circling after 30 days of grafting, whereas the differentiated NB cells were ineffective in producing such an effect.
The specific aims of this renewal application are as follows: a) to determine the long-term efficacy of grafted immortalized rat DA- producing nerve cells in improving the neurological deficits of rats with 6-OHDA lesions; b) to establish and characterize human immortalized DA-producing nerve cells in vitro, and then test their efficacy in improving neurological deficits of rats with 6-OHDA lesions; c) to establish hybrid cells by fusing DA-producing immortalized nerve cells with glia cells, characterize them, and then test their efficacy in improving neurological deficits of rats with 6-OHDA lesions; and d) to study the induction of morphological and biochemical differentiated functions in parent and hybrid dopamine-producing cells in vitro, and then test their efficacy for improving neurological deficits in rats with 6-OHDA lesions. Future studies will focus on testing the efficacy of immortalized DA-producing nerve cells first in MPTP-treated monkeys with the ultimate goal of eventually treating patients with advanced Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029982-09
Application #
6151584
Study Section
Neurology A Study Section (NEUA)
Program Officer
Oliver, Eugene J
Project Start
1992-01-01
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2002-01-31
Support Year
9
Fiscal Year
2000
Total Cost
$405,887
Indirect Cost
Name
University of Colorado Denver
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Clarkson, E D; Zawada, W M; Bell, K P et al. (2001) IGF-I and bFGF improve dopamine neuron survival and behavioral outcome in parkinsonian rats receiving cultured human fetal tissue strands. Exp Neurol 168:183-91
Prasad, K N; Hovland, A R; Cole, W C et al. (2000) Multiple antioxidants in the prevention and treatment of Alzheimer disease: analysis of biologic rationale. Clin Neuropharmacol 23:13-Feb
Kumar, A; Hovland, A R; La Rosa, F G et al. (2000) Relative sensitivity of undifferentiated and cyclic adenosine 3',5'-monophosphate-induced differentiated neuroblastoma cells to cyclosporin A: potential role of beta-amyloid and ubiquitin in neurotoxicity. In Vitro Cell Dev Biol Anim 36:81-7
Kaddis, F G; Clarkson, E D; Bell, K P et al. (2000) Co-grafts of muscle cells and mesencephalic tissue into hemiparkinsonian rats: behavioral and histochemical effects. Brain Res Bull 51:203-11
Prasad, K N; Cole, W C; Kumar, B (1999) Multiple antioxidants in the prevention and treatment of Parkinson's disease. J Am Coll Nutr 18:413-23
Hovland, A R; La Rosa, F G; Hovland, P G et al. (1999) Cyclosporin A regulates the levels of cyclophilin A in neuroblastoma cells in culture. Neurochem Int 35:229-35
Clarkson, E D; Edwards-Prasad, J; Freed, C R et al. (1999) Immortalized dopamine neurons: A model to study neurotoxicity and neuroprotection. Proc Soc Exp Biol Med 222:157-63
Clarkson, E D; Zawada, W M; Adams, F S et al. (1998) Strands of embryonic mesencephalic tissue show greater dopamine neuron survival and better behavioral improvement than cell suspensions after transplantation in parkinsonian rats. Brain Res 806:60-8
Clarkson, E D; La Rosa, F G; Edwards-Prasad, J et al. (1998) Brain contains inhibiting factors specific to the large T-antigen gene. Cancer Lett 122:31-6

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