Human Neural Stem Cells in Primate Parkinson's Model

描述（由申请人提供）：本项目将研究假设 人类神经干细胞（hNSCs）移植到猴子体内可以使 神经毒素1-甲基-4-苯基-1，2，3，6引起的帕金森综合征 四氢吡啶（MPTP）。这些原始的、未定型的多能细胞可以 大量繁殖，然后安全地分化成大多数细胞， 神经系统的类型，包括产生多巴胺的神经元。神经干细胞迁移 来填充正在发育或退化的大脑区域， 功能正确和有效的重建。初步研究显示 hNSC在胎儿、新生儿、婴儿和成人脑中的植入 猴子至少一个月多巴胺耗尽的成年猴子显示， 移植物衍生的酪氨酸羟化酶阳性细胞和适当迁移 从注射部位转移到多巴胺缺乏的区域 该项目将在猴子中测试假设：（1）hNSCs将存活， 分化和整合在正常成年猴子的大脑中， 免疫排斥或有害过度生长;（2）hNSC将消除 MPTP治疗后帕金森病，并认为存在多巴胺损伤 将影响它们的分布和命运。将识别NSC， 使用遗传标记、免疫组织化学和多突触标记进行定量。 束追踪以下将在正常情况下进行表征和比较 猴和MPTP后的猴：hNSC存活，迁移，细胞分裂， 分化、连接性、免疫原性、a 转基因（LacZ），细胞凋亡和宿主环境对所有这些的影响。在 多巴胺耗尽的帕金森病猴子，多巴胺及其代谢物 浓度，多巴胺转运体放射自显影，行为逆转 帕金森症，剂量效应和突触连接将被研究超过 7天、1个月、3个月、6个月和12个月的时间过程。还将进行比较 与原代胎儿腹侧中脑组织移植的影响， 帕金森病猴先前和平行研究。 这些研究将促进我们对神经生物学和安全性的理解。 在已建立的临床相关灵长类动物模型中的人神经干细胞 帕金森氏病，如果成功，支持安全的临床研究， 帕金森病患者的未来。结果也将提前 了解研究和治疗各种疾病的有用方法 神经系统的神经变性、遗传和创伤性病症。

DESCRIPTION (provided by applicant): This project will study the hypothesis that human neural stem cells (hNSCs) implanted into monkeys can normalize parkinsonism resulting from the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). These primordial, uncommitted, pluripotent cells can be propagated in large numbers and then safely differentiated into most cell types of the nervous system, including dopamine-producing neurons. NSCs migrate to populate developing or degenerating brain regions, perhaps allowing a more functionally correct and effective reconstruction. Pilot studies now show engraftment of hNSCs in the brain of fetal, neonatal, infant, and adult monkeys, for at least a month. Dopamine depleted adult monkeys showed graft-derived tyrosine hydroxylase positive cells and appropriate migration from the site of injection to dopamine-depleted areas. This project will test hypotheses in monkeys: (1) that hNSCs will survive, differentiate, and integrate in the brain of normal adult monkeys without immunological rejection or harmful overgrowth; (2) that hNSCs will eliminate parkinsonism after MPTP treatment, and that the presence of dopamine injury will influence their distribution and fate. NSCs will be identified and quantitated using genetic markers, immunohistochemistry, and multi-synaptic tract tracing. The following will be characterized and compared in normal monkeys and monkeys after MPTP: hNSC survival, migration, cell division, differentiation, connectivity, immunogenicity, stability of expression of a transgene (LacZ), apoptosis, and effect of host environment on all of these. In the dopamine-depleted parkinsonian monkey, dopamine and its metabolite concentrations, autoradiography of dopamine transporters, behavioral reversal of parkinsonism, dose effects, and synaptic connections will be studied over time courses of 7 days, 1, 3, 6, and 12 months. Comparisons will also be made with effects of primary fetal ventral mesencephalic tissue transplants in parkinsonian monkeys from prior and parallel studies. These studies will advance our understanding of the neurobiology and safety of human neural stem cells in a well established clinically relevant primate model of Parkinson's disease, and, if successful, support safe clinical studies in patients with Parkinson's disease in the future. The results will also advance understanding of useful methods for studying and treating a broad range of neurodegenerative, genetic, and traumatic conditions of the nervous system.