MORPHOLOGICAL ANALYSES OF NEURAL AND PARANEURAL GRAFTS

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The specific aim of this project is to identify, characterize, and determine the potential for use of alternative sources of donor tissue for transplantation in animal models of Parkinson's disease. Because of the ethical, moral, and legal questions surrounding the use of fetal tissues as potential grafts, alternate sources of donor tissue need to be found which will ameliorate the motor deficits caused by Parkinson's disease. This specific aim will be addressed in light of two working hypotheses: (a) Neural crest derivatives belonging to the sympathoadrenal lineage possess inherent phenotypic characteristics which suggest they would be excellent candidates for neural transplantation; and (b) The adult adrenergic derivatives of this lineage, when transplanted into the denervated striatum, will significantly reverse the functional deficits, survive in the host, and continue to elaborate catecholamines. These working hypotheses will be tested both in vitro and in vivo using the three adult adrenergic derivatives of the lineage: (a) principal neurons; (b) adrenal chromaffin cells; and (c) SIF, or glomus cells. The growth and phenotypic differentiation of these cells will be studied using neurochemistry (HPLC), immunohistochemistry, histofluorescence, and scanning and transmission electron microscopy. For my in vivo experiments, the 6-OHDA treated rat model of Parkinson's disease will be used to study the survival and differentiation of implanted cells and tissue fragments of the sympathoadrenal lineage. Moreover, the host response to transplants will be studied ultrastructurally with respect to reactive gliosis, macrophage activity, and the integrity of the blood-brain barrier. In conjunction with these rodent experiments, I will collaborate with those projects using the MPTP primate model of Parkinson's disease by providing EM analysis of their transplants. The behavioral, neurochemical, and morphological results of the rodent studies will be compared with those obtained from the primate experiments. The long-term goals of this work will be to determine the potential of sympathoadrenal cells for use as transplants in humans. The fundamental knowledge gained from these transplantation studies may provide practical clinical approaches to promote recovery from Parkinson's disease and other CNS debilitating diseases such as Alzheimer's disease, Huntington's chorea and CNS trauma.