Stem Cell Adaptability in Parkinson's Disease

Clinical trials have provided encouraging evidence that grafts of fetal dopamine neurons are an effective therapeutic approach toward counteracting the symptoms of Parkinson's disease (PD). Modest therapeutic benefits are observed in grafted patients despite clinical and experimental evidence that survival of grafted cells is low and graft reinnervation is incomplete. ~ecently it was demonstrated embryonic stem cells (ESe) could be converted to dopamine neurons in culture and, when implanted into animals with experimental Parkinson's disease, produced a degree of functional recovery similar to implants of fetal dopamine neurons. Because dopamine neurons derived from ESC are generated in cultures by manip.ulating various growth factors, it still remains to be determine whether or not ESC-derived dopamine neurons have a similar phenotype as normal developing dopaminergic neurons. Moreover, the dynamic microenviroment of the brain, particularly the neurotrophic enviroment, may alter the survival, function, and even the fate of transplanted ESC. The objective of the initial studies will determine whether or not ESC-derived dopamine neurons retain various cellular markers that are critical to the survival and maintenance of developing and mature dopamine neurons. In particular, studies will focus on the identification of neurotrophic factors and neurotrophic factor receptors on ESC-derived dopamine neurons that are typically associated with normal dopamine neurons. We will then identify and measure various growth factors within the host brain that may influence the fate of transplanted ESC, and assess how these factors change following a degenerative lesion of the nigrostriatal and/or during aging. Studies will be designed to vary the neurotrophic environment of the host brain in order to determine the adaptability of implanted ESC; conditions will be varied using various lesion models and gene therapy techniques to alter the expression of neurotrophic factors. The variable of host age on ESC-derived dopamine neuron adaptability will be studied.