Parkinson's disease (PD) is a neurodegenerative disorders characterized by a progressive loss of dopaminergic neurons of substantia nigra pars compacta with motor dysfunctions. The etiology of PD is yet unknown, and there is no cure available. Although various pharmacotherapies are modestly successful, late complications of the therapies limit the ultimate utility. We propose the use of genetically modified primary skin fibroblasts that produce catecholamines or neurotrophic factors as donor cells for grafting in rat models of PD. The primary dermal fibroblasts can be biopsied easily and grown well in culture. These primary fibroblast can be genetically modified by retroviral vectors with high efficiency. Tyrosine hydroxylase, aromatic L-amino acid decarboxylase, basic fibroblast growth factor, and brain derived neurotrophic factor will be introduced by this method. The transduced fibroblasts will be examined in vitro to characterize the expression of these transgenes and their biological functions. These cells will then be grafted in the brain to assess the survival, host reactions, and transgene expression in vivo. Once fully characterized, these cells will be studied for functional effects in rat models of PD. The catecholamine-producing cells will be tested for their ability to ameliorate the apomorphine-induced rotational behavior in rats with unilateral lesions of the substantia nigra. The neurotrophic factor- producing fibroblasts will be studied for their ability to promote sprouting and survival of the remaining dopaminergic neurons, and their effect on behavioral recovery. In the future, combinations of both neurotransmitter replacement and neurotrophic factor delivery strategies will also be studied.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG008514-11
Application #
2732509
Study Section
Special Emphasis Panel (NSS)
Project Start
1989-07-01
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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