Fetal dopamine neurons are implanted into the brains of Parkinson's disease patients in an effort to replace lost neurons and restore dopamine levels. Death of 95% of the transplanted neurons limits the usefulness of this experimental therapy. Transplanted dopamine neurons die in part by apoptosis (programmed cell death) and to a lesser extent by necrosis. This finding opens the exciting possibility that signaling pathways leading to the initiation and execution of the death program can be blocked while signaling pathways that protect against apoptosis can be activated to reduce neuronal death. In vitro experiments have shown that p38 mitogen-activated protein (MAP) kinase is activated during apoptosis in primary neurons and that a specific inhibitor of p38 MAP kinase rescues neurons from apoptotic cell death. Since apoptosis occurs in neural grafts during transplantation, we hypothesize that specific inhibitors of p38 MAP kinase will block apoptosis of fetal dopaminergic neurons transplanted into the striatum of Parkinsonian rats resulting in increased neuronal survival, better reinnervation of the striatum, and improved motor behavior. IGF-1, bFGF, insulin and GDNF also rescue cultured dopaminergic neurons from apoptosis. Based on studies in other types of neurons, these growth factors are thought to work by either stimulating antiapoptotic pathways, (i.e., IGF-1 stimulation of Akt) or inhibiting proapoptotic pathways ( i.e., insulin inhibition of p38 MAP kinase). Since there are multiple pathways regulating apoptosis, we predict that combination of growth factors and inhibitors of p38 MAP kinase will provide additive protection of the transplanted grafts against apoptosis. Moreover, by further delineating the signaling pathways that mediate the antiapoptotic effects of the above growth factors, new cellular targets for therapy can be defined.
The specific aims of the proposal are to: #1. Determine if specific inhibitors of p38 MAP kinase improve transplantation of fetal dopaminergic neurons. #2. Determine if the combination of p38 MAP kinase inhibitor and growth factors provides additive protection against apoptosis in transplanted tissue grafts. #3. Define the signaling pathways by which IGF-1, bFGF, insulin and GDNF promote survival of dopaminergic cells. Results from these studies will provide a basis for translating the use of p38 inhibitors and growth factors in transplantation to human studies and will provide new cellular targets that can be manipulated to prevent or arrest neuronal apoptosis.
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