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经被患者的研究部分证实，但移植可能存在需要解决的重大问题。功能改善似乎是可变的，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，但仍不完全。假设移植的局限性源于移植物的不足，原因是移植细胞存活率低，缺乏关键的生长因子，或移植物的放置和分布不具生理性。该计划建议用可能改善功能益处的策略来检验这些假设--这是对MPTP帕金森病猴子的所有研究的主要结果衡量标准。 项目一以移植后早期细胞死亡为目标，采用细胞黏附因子、甲磺酸氮杂环丙烷、褪黑素、血管内皮生长因子和cAMP减少氧化应激、缺氧/缺血和细胞凋亡的策略。项目二专注于由富含星形胶质前体细胞的胎儿纹状体产生的生长因子，或从被包裹的细胞输送的生长因子GDNF。将测试一种优化的方法，以确定联合方法在年轻成年猴子和老年猴子身上的益处。项目三旨在 通过将黑质(SN)前体组织植入黑质(SN)，并使用联合移植的胎儿纹状体细胞或GDNF交付，将其生长引导到靶区，从而恢复相关的多巴胺通路。行为改善的持续时间和稳定性、可能的运动障碍或其他毒性效应将进行为期三年的评估，并与纹状体移植进行比较。量化的行为效应将与生化和 死后的形态测量。这些研究可能有助于提高移植物的存活率、神经再支配，以及有缺陷的多巴胺回路的生理性恢复和功能正常化。虽然已经在啮齿动物身上做了大量的前期工作，而且由于无法在人类身上完成具有可验证结果的明确的对照实验，但应该在猴子的MPTP模型中测试假说和安全性。这些项目将由项目调查人员联合开展，利用一个独特的灵长类移植实验室(核心A)的资源和共享结果方法，所有这些都由一个计划支持单位(核心B)协调。了解胎儿前体细胞的存活和生长也可能有助于更好地理解其他潜能的可塑性和功能。 替代细胞，如干细胞，并与帕金森氏症以外的其他人类神经退行性或创伤性疾病相关。

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.