Improving neural graft function in parkinsonian monkeys.

胎儿神经移植在灵长类帕金森模型中的益处已部分被患者研究证实，但移植可能存在值得解决的重大问题。功能改善是可变的，在老年患者中效果较差，尽管多巴胺的产生有一些明显的增加，但功能改善是不完全的。假设移植的局限性是由于移植物不足，由于移植细胞存活率低，缺乏关键生长因子，或非生理性移植物的放置和分布。该项目建议用可能提高功能效益的策略来测试这些假设——这是所有MPTP帕金森猴研究的主要结果衡量标准。

The benefits of fetal neural transplantation in primate Parkinson's models have been partially confirmed by studies in patients, but transplantation may have significant problems which should be addressed. Functional improvement appears variable, less effective in older patients, and incomplete in spite of some apparent increases in dopamine production. The hypotheses are that transplantation's limitations result from inadequate grafts, due to poor survival of implanted cells, lack of critical growth factors, or nonphysiological graft placements and distribution. This program proposes to test these hypotheses with strategies which may improve functional benefits--the primary outcome measure of all studies in MPTP parkinsonian monkeys. Project One targets early cell death after grafting, with strategies to reduce oxidant stress, hypoxia/ischemia, and apoptosis using cell adhesion factors, the lazaroid tirilizad mesylate, melatonin, vascular endothelial growth factor, and cAMP. Project Two focuses on growth factors produced by fetal striatum enriched in astrocyte progenitor cells, or the growth factor, GDNF, delivered from encapsulated cells. An optimized method will be tested to determine benefits of combined methods in young adult and aged monkeys. Project Three aims to restore the relevant dopamine pathways by implantation of substantia nigra (SN) precursor tissue into SN and directing its outgrowth to the target areas, using co-grafted fetal striatal cells, or GDNF delivery. Duration of and stability of behavioral improvement, possible dyskinesias, or other toxic effects will be evaluated for three years and compared with striatal grafts. Quantitative behavioral effects will be correlated with biochemical and morphological measurements post-mortem. These studies may contribute to improving graft survival, reinnervation, and physiological restoration of the defective dopamine circuits and normalizing function. Although considerable preliminary work has been done in rodents, and because definitive controlled experiments with verifiable outcomes cannot be accomplished in humans, hypotheses and safety should be tested in the MPTP model in monkeys. The projects will be undertaken jointly by the program investigators, applying the resources of a unique primate transplantation laboratory (Core A) and shared outcome methodologies, all coordinated by a program support unit (Core B). Understanding of fetal precursor cell survival and outgrowth may also lead to improved understanding of the plasticity and function of other potential replacement cells, such as stem cells, and be relevant to other human neurodegenerative or traumatic conditions in addition to Parkinson's disease.