In project 1, Dr. Gash and his associates will (i) study the processes underlying behavioral recovery following grafting into the CNS and (ii) analyze and evaluate cograft approaches for the treatment of Parkinson's disease using rodent and nonhuman primate models of parkinsonism. The studies to be conducted over the next five years include: 1. Analysis of the factors promoting adrenal chromaffin cell survival in adrenal medulla/peripheral nerve cografts. Cografting adrenal/medulla with minced peripheral nerve has been shown to increase grafted chromaffin cell survival four to eightfold in rodents and nonhuman primates. This experimental series will analyze the role of technical factors and different cell types found in the peripheral nerve on chromaffin cell viability using Fisher 344 rats with selective nigrostriatal lesions. 2. Characterization of a more complete nonhuman primate model of Parkinson's disease. Studies in progress indicate that Rhesus monkeys receiving staged bilateral nigrostriatal lesions via intracarotid artery infusions of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) more closely match the constellation of symptoms seen in human parkinsonism than unilaterally lesioned animals. Experiments will be conducted to determine if the bilaterally impaired animals provide an improved model for investigating parkinsonism and its treatment. 3. Compare the efficacy of adrenal medulla-peripheral nerve cografts to adrenal medulla only grafts. Earlier studies have shown that adrenal chromaffin cells autografted into the primate striatum do not survive well. However, chromaffin cell survival can be significantly enhanced by cografting along with trophic factor producing tissues such as peripheral nerve. This study is designed to determine if increasing chromaffin cell survival via the cograft approach significantly (delta >25%, P<0.05) improves behavioral recovery. 4. Analysis and correlation of graft and host features in control and implanted Rhesus monkeys hypothesized to be important in behavioral recovery. Analysis will include quantitation of implanted chromaffin cell survival, evaluation of host regenerative responses by immunohistochemical and tract tracing and quantitative morphometric analysis of surviving host A8, A9 and A10 dopamine neurons. These results should lead to a better understanding of the CNS changes underlying behavioral recovery in parkinsonian animals and quite possibly improved therapeutic approaches for treating Parkinson's disease patients.
Showing the most recent 10 out of 37 publications
