Neural Stem Cells Grafts in Primate Models of Parkinsons

帕金森灵长类动物模型中的神经干细胞移植

• 批准号: 6625939
• 负责人: LORRAINE IACOVITTI
• 金额: $ 19.63万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6625939
• 关键词: Macaca mulatta; Parkinson's disease; cell cycle; cell differentiation; cell migration; cell transplantation; disease /disorder model; male; nerve stem cell; nervous system disorder therapy; neurons; nonhuman therapy evaluation

DESCRIPTION (provided by applicant) One promising new therapy for Parkinson's Disease (PD) involves the replacement of degenerated nigrostriatal neurons with those derived from transplanted fetal mesencephalic tissue. Although this approach has often yielded remarkable recovery of function in rats and monkeys, results in clinical trials with PD patients have been less consistent. At issue, is the relative inability to standardize a number of critical factors in human fetal transplants, including the age, type, number and integrity of cells being grafted. Consequently, finding more reliable sources of dopaminergic (DA) tissue for transplantation has become increasingly important. One direction has been to search for a line of readily available, well-characterized, continually self-renewing stem or precursor cells that possess the capacity to differentiate, ideally spontaneously and without need of genetic manipulation, into DA neurons, thus providing an inexhaustible and uniform source of replacement tissue. Towards this end, our preliminary findings demonstrate that grafts of embryonic mouse neural stem cells of the C17.2 cell can differentiate exclusively into neurons, which in a majority of cases, can express DA traits when transplanted into the brain of a Parkinsonian rat. In addition, we now have available two human NSC lines (HNSC.100 and HSP-2) which are being studied in vitro and in rat models of PD. Therefore, the goal of the present proposal is to move a step closer to the clinic by testing the utility of both mouse and human stem cells in a non-human primate model of PD. Our specific goals for this proposal are twofold: 1) Determine whether mouse NSCs behave in a primate model as they do in a rat model of PD; and 2) Determine whether human NSCs also differentiate, integrate and function as DA neurons when transplanted into the MPTP-treated monkey. The ultimate goal of this research program is a fuller understanding of the cellular and molecular processes regulating the differentiation of DA traits in stem cells and application of that knowledge to transplantation strategies for the treatment of Parkinson's Disease.

描述(由申请人提供) 治疗帕金森氏病(PD)的一种有希望的新疗法涉及替代疗法 变性黑质纹状体神经元与移植胎儿来源神经元的比较 中脑组织。尽管这种方法通常会产生显著的效果 帕金森病临床试验结果显示，大鼠和猴子的功能恢复 患者的态度一直不太一致。争论的焦点是相对没有能力 标准化人类胚胎移植的一些关键因素，包括 被移植细胞的年龄、类型、数量和完整性。因此， 为移植寻找更可靠的多巴胺能组织来源 已经变得越来越重要。一个方向是寻找一条线 容易获得的、特征良好的、不断自我更新的茎或 具有分化能力的前体细胞，理想情况下 自发地，不需要基因操作，进入DA神经元，从而 提供取之不尽、用之不竭的替代组织来源。朝向 为此，我们的初步发现表明，胚胎小鼠的移植 C17.2细胞的神经干细胞可以完全分化为神经元， 在大多数情况下，当移植到 帕金森氏症大鼠的大脑。此外，我们现在有两个人类NSC 正在进行体外和大鼠模型研究的HNSC.100和HSP-2株 警局的。因此，本提案的目标是更接近于 通过测试小鼠和人类干细胞在 帕金森病的非人灵长类动物模型。我们对这项提议的具体目标是 两个方面：1)确定小鼠神经干细胞在灵长类动物模型中的行为是否与它们一样 在帕金森病大鼠模型中；以及2)确定人类神经干细胞是否也分化， 移植到MPTP处理的神经元中整合并发挥DA神经元的功能 猴子。这项研究计划的最终目标是更全面地了解 调节多巴胺分化的细胞和分子过程 干细胞的特性及其在移植中的应用 帕金森氏症的治疗策略。