The past 15 years have seen substantial progress in research on embryonic dopamine cell transplantation in animals. These experiments have led to neurotransplantation as a developing therapy for humans with advanced Parkinson's disease. Nearly every principle established in the rat has proven applicable to humans. Rats defined the developmental stage suitable for transplant and demonstrated that behavioral effects occur only after process outgrowth and reinnervation of the striatum. Man has become the species with the longest surviving transplants. Despite this remarkable progress, transplants have not cured Parkinsonian syndromes in man or experimental animals. In animals, restoration of learned behaviors has been difficult to achieve. Poor survival of dopamine cells and limited neurite outgrowth are the major shortcomings of neurotransplantation. As few as 5% to 10% of dopamine cells survive. In an attempt to improve neural transplantation, the PI has developed strategies for reducing dopamine cell death in vitro. In previous experiments, they have shown that insulin-like growth factor (IGF-1), basic fibroblast growth factor (bFGF), and glial derived neurotropic factor (GDNF) have additive effects for promoting dopamine cell survival in vitro. The PI has demonstrated that improved survival is the result of apoptotic programmed cell death. In experiments in aged monkeys, we have found that dopamine cell survival is much worse than in younger animals. In this grant proposal we will try to improve transplants in young and aged rats through a systemic study of cell survival after transplant. Hypothesis I: Apoptotic programmed cell death in the first 14 days after neural transplantation will account for the majority of dopamine cell death in both young (10 to 12 weeks of age) and old (18 months) male Fisher 344 rats. Hypothesis II: Long term cell survival, (3 months), will be less good in aged animals than in young animals. Hypothesis III: Embryonic striatal cotransplants or cotransplants of cells genetically modified to produce the growth factors IGF-1, bFGF, and GDNF will improve dopamine cell survival both in early (1-14 days) and late (3 months) times after transplant. If there is relatively poor long term survival of dopamine cell transplants in aged animals, the investigators expect that growth factors or striatal cotransplants will have relatively greater value in aged than in young animals. If these experiments are successful, similar strategies could be directly extended to humans receiving embryonic dopamine neurotransplants for Parkinsons' disease.
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