HUMAN NEURAL STEM CELLS IN PRIMATE PARKINSON'S MODEL

描述：(改编自申请者摘要)此 多中心/多研究人员发起的提案将调查 人神经干细胞(HNSCs)移植到亚人体内 灵长类动物的大脑。特别关注的是这样一种假设，即这些 细胞可以完全正常化由MPTP损伤引起的猴子帕金森症。 因此，我们将研究三个相关的假设。首先是hNSCs 将在正常猴子大脑中存活，而不会出现免疫排斥反应或 破坏性的过度生长。接下来，该提案将检验hNSC的假设 可以逆转MPTP相关的运动障碍，而多巴胺的存在 损伤会影响这些供体细胞的分布和命运。最后 该项目的一部分是为了证明基因工程 HNSCs可通过以下修饰改善帕金森病的功能逆转 (A)通过一个枢纽增加分化的多巴胺能细胞的产量 转录因子，(B)表达GDNF，和(C)过表达黏附 分子L1，从而影响细胞的迁移和分布 可能使更正常的多巴胺能回路得以重建。 这些研究将涉及当代和多学科的广泛领域。 神经解剖学、分子生物学和行为评估相结合的方法 具有先进的临床诊断方法。

DESCRIPTION: (Adapted from applicant's abstract) This multicenter/multinvestigator-initiated proposal will investigate the biology of human neural stem cells (hNSCs) following transplantation into the subhuman primate brain. Particular attention is directed at the hypothesis that these cells can fully normalize parkinsonism in monkeys resulting from MPTP lesions. Three related hypotheses will thus be investigated. The first is that hNSCs will survive in the normal monkey brain without immunological rejection or destructive overgrowth. Next, the proposal will test the hypothesis that hNSCs can reverse MPTP-associated motor deficits and that the presence of dopamine injury will influence the distribution and fates of these donor cells. The last part of the project is intended to demonstrate that genetic engineering of hNSCs can improve the functional reversal of parkinsonism by modifications that (a) increase the yield of differentiated dopaminergic cells via a pivotal transcription factor, (b) express GDNF, and (c) overexpress the adhesion molecule L1 which influences migration and distribution of cells thereby possibly permitting a more normal dopaminergic circuitry to be reconstructed. These studies will entail a wide spectrum of contemporary and multidisciplinary methods in neuroanatomy, molecular biology, and behavioral assessment coupled with advanced clinical diagnostic approaches.