Human Neural Stem Cells in Primate Parkinson's Model

灵长类帕金森病模型中的人类神经干细胞

• 批准号: 6729098
• 负责人: DONALD EUGENE REDMOND
• 金额: $ 87.72万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729098
• 关键词: Parkinson' s disease; Primates; apoptosis; autoradiography; cell differentiation; cell migration; cell proliferation; cyclosporines; dopamine; electron microscopy; fluorescent in situ hybridization; genetic markers; human tissue; immunocytochemistry; immunosuppression; longitudinal animal study; methylphenyltetrahydropyridine; nerve stem cell; nervous system disorder therapy; neurobiology; nonhuman therapy evaluation; phenotype; single photon emission computed tomography; stem cell transplantation; terminal nick end labeling

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.

描述（由申请人提供）：该项目将研究假设 植入猴子的人神经干细胞（HNSC）可以正常化 由神经毒素1-甲基-4-苯基1,2,3,6产生的帕金森氏症 四氢吡啶（MPTP）。这些原始的，不承诺的多能细胞可以 大量传播，然后安全地分化为大多数单元 神经系统的类型，包括产生多巴胺的神经元。 NSC迁移 填充发展或退化的大脑区域，也许允许更多 在功能上正确有效的重建。试点研究现在表明 胎儿，新生儿，婴儿和成人大脑中的HNSC植入 猴子，至少一个月。多巴胺耗尽的成年猴子显示 移植衍生的酪氨酸羟化酶阳性细胞和适当的迁移 从注射部位到耗尽多巴胺的区域。 该项目将在猴子中检验假设：（1）HNSC将生存， 区分并整合在没有正常成年猴子的大脑中 免疫拒绝或有害的过度生长； （2）HNSC将消除 MPTP治疗后的帕金森氏症，多巴胺损伤的存在 将影响他们的分布和命运。 NSC将被识别，并且 使用遗传标记，免疫组织化学和多突触 道图。以下将被表征和比较 MPTP之后的猴子和猴子：HNSC生存，迁移，细胞分裂， 分化，连通性，免疫原性，表达的稳定性 转基因（LACZ），凋亡以及宿主环境对所有这些的影响。在 多巴胺贫血的帕金森尼猴，多巴胺及其代谢物 浓度，多巴胺转运蛋白的放射自显影，行为逆转 将研究帕金森氏症，剂量效果和突触连接 7天，1、3、6和12个月的时间课程。还将进行比较 与原发性胎儿腹脑室内组织移植的作用 来自先前和平行研究的帕金森猴。 这些研究将提高我们对神经生物学和安全性的理解 人类神经干细胞在建立的临床相关的灵长类动物模型中 帕金森氏病，如果成功，请支持安全的临床研究 帕金森氏病的患者将来。结果也将进步 了解有用的方法，用于研究和治疗广泛的 神经系统的神经退行性，遗传和创伤状况。