Neural Stem Cells Grafts in Primate Models of Parkinsons

描述（由申请人提供） 帕金森病（PD）的一种有前途的新疗法涉及替代 与移植胎儿黑质纹状体神经元的比较 中脑组织尽管这种方法经常产生显著的效果， 大鼠和猴的功能恢复，PD临床试验结果 病人的情况不太一致。争论的焦点是， 标准化人类胚胎移植中的一些关键因素，包括 移植细胞的年龄、类型、数量和完整性。因此，委员会认为， 为移植寻找更可靠的多巴胺能（DA）组织来源 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， 自发地，不需要遗传操作，进入DA神经元，因此， 提供了一个取之不尽的和均匀的替代组织来源。朝向 为此，我们的初步研究结果表明，胚胎小鼠的移植物， C17.2细胞的神经干细胞可专一性分化为神经元， 在大多数情况下，当移植到 帕金森大鼠的大脑此外，我们现在有两个人类神经干细胞 细胞系（HNSC.100和HSP-2），其正在体外和大鼠模型中进行研究 的PD。因此，本提案的目标是更进一步， 通过测试小鼠和人类干细胞在临床上的效用， PD的非人灵长类动物模型。我们提出这项建议的具体目标是 双重：1）确定小鼠NSC在灵长类动物模型中是否表现为它们所表现的那样 在PD大鼠模型中;和2）确定人NSC是否也分化， 当移植到MPTP处理的神经元中时， 猴子.这项研究计划的最终目标是更全面地了解 调节DA分化的细胞和分子过程 干细胞特性及其在移植中的应用 帕金森病的治疗方法

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.