NRSA Fellowship for Ziemba: Reconstruction of the nigrostriatal pathway

The long-term objective of this research proposal is to develop a means to reconstruct the neural circuit that degenerates in Parkinson's disease (PO) - that is, the nigrostriatal pathway. While current therapy (Ievodopa treatment) for PO may alleviate symptoms for a while, there is still no way to halt or reverse the neurodegeneration. Since 1% of the population over the age of 65 is affected by PO, and the prevalence increases with increasing age, research into better therapies and an eventual cure for PO is important for our aging population. Cellular replacement is not a new idea in PO research, but this proposal differs from most previous efforts by attempting an anatomically and physiologically correct reestablishment of the nigrostriatal pathway, effecting a more complete behavioral recovery. Molecular cues to guide grow1h of dopaminergic neurons will be identified in vitro, and adenoviral vectors will be used to express these molecules between the substantia nigra (SN) and the striatum in hemiparkinsonian rats. When dopaminergic neurons are subsequently transplanted into the SN, their axons should grow along the grow1h-supportive pathway, ending in the striatal target. Success will be evaluated with detailed histological and behavioral analyses.