Improving neural graft function in parkinsonian monkeys.

改善帕金森猴的神经移植功能。

• 批准号: 6917791
• 负责人: DONALD EUGENE REDMOND
• 金额: $ 117.98万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917791
• 关键词: Parkinson' s disease; dopamine; embryo /fetus tissue transplantation; nervous system transplantation; nonhuman therapy evaluation

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.

胎儿神经移植在灵长类帕金森病模型中的益处已通过对患者的研究得到部分证实，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，但并不完全。假设移植的局限性是由于移植物不足，由于植入细胞的存活率差，缺乏关键的生长因子，或非生理性移植物的放置和分布。该计划提出了测试这些假设的策略，可能会提高功能的好处-MPTP帕金森病猴的所有研究的主要结果的措施。 项目一的目标移植后早期细胞死亡，与战略，以减少氧化应激，缺氧/缺血，细胞凋亡使用细胞粘附因子，lazaroid替利扎德甲磺酸盐，褪黑激素，血管内皮生长因子，和cAMP。项目二的重点是由富含星形胶质细胞祖细胞的胎儿纹状体产生的生长因子，或由包囊细胞递送的生长因子GDNF。将对优化方法进行检测，以确定联合方法在年轻成年猴和老年猴中的获益。项目三旨在 通过将黑质（SN）前体组织植入SN并使用共移植的胎儿纹状体细胞或GDNF递送将其生长导向靶区域来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作用将评估三年，并与纹状体移植物进行比较。定量行为效应将与生物化学和 死后的形态测量这些研究可能有助于改善移植物的存活率，神经再支配，以及有缺陷的多巴胺回路的生理恢复和正常化功能。虽然已经在啮齿动物中进行了大量的初步工作，但由于无法在人类中完成具有可验证结果的确定性对照实验，因此应在猴子的MPTP模型中测试假设和安全性。这些项目将由项目研究人员联合开展，应用独特的灵长类动物移植实验室（核心A）的资源和共享的结果方法，所有这些都由项目支持单位（核心B）协调。了解胎儿前体细胞的存活和生长，也可能导致改善对其他潜在的可塑性和功能的理解。 替代细胞，如干细胞，并且与除了帕金森病之外的其他人类神经变性或创伤性病症相关。