Human Neural Stem Cells in Primate Parkinson's Model

描述(由申请者提供)：这个项目将研究假设 人类神经干细胞(HNSCs)移植到猴子体内可以正常化 神经毒素1-甲基-4-苯基-1，2，3，6引起的帕金森病 四氢吡啶(MPTP)。这些原始的、未固定的、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。NSC迁移 以填充发育中或退化的大脑区域，也许允许更多 功能正确有效的重建。试点研究现在表明 人神经干细胞在胎儿、新生儿、婴儿和成人脑内的植入 猴子，至少一个月。多巴胺耗竭的成年猴子显示 移植物来源的酪氨酸羟化酶阳性细胞及其适当迁移 从注射部位到多巴胺耗竭区域。 这个项目将在猴子身上测试假设：(1)hNSCs将存活， 分化，并整合到正常成年猴子的大脑中，没有 免疫排斥或有害的过度生长；(2)hNSCs将消除的 MPTP治疗后帕金森病与多巴胺损伤的存在 将影响它们的分布和命运。将确定NSC，并 使用遗传标记、免疫组织化学和多突触进行定量 轨迹追踪。以下内容将在正常情况下进行描述和比较 猴与猴MPTP后：hNSC存活、迁移、细胞分裂、 A基因的分化、连通性、免疫原性、表达稳定性 转基因(LacZ)、细胞凋亡以及寄主环境对这些的影响。在……里面 多巴胺耗竭帕金森病猴、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 帕金森氏症、剂量效应和突触连接的研究 疗程为7天、1个月、3个月、6个月和12个月。还将进行比较 原发胎儿腹侧中脑组织移植的疗效观察 来自先前和平行研究的帕金森病猴子。 这些研究将促进我们对神经生物学和安全性的理解。 已建立的临床相关灵长类动物模型中的人类神经干细胞 帕金森氏症，如果成功，将支持安全的临床研究 帕金森氏症患者的未来。结果也将向前推进 对广泛研究和治疗的有用方法的理解 神经系统退行性、遗传性和创伤性疾病。

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.