Human embryonic stem cell derived midbrain dopamine neurons

人胚胎干细胞来源的中脑多巴胺神经元

基本信息

批准号：
7342836
负责人：
LORENZ P. STUDER
金额：
$ 39.94万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-24 至 2010-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposal is to identify the factors that limit in vivo survival and function of human ES (hES) derived dopamine (DA) neurons in preclinical models of Parkinson's disease (PD). Preliminary work in our lab has provided high-yield protocols for the derivation of midbrain DA neurons from hES cells. However, pilot transplantation studies of hES cell derived DA neurons in rodent and non-human primates suggest poor in vivo survival and maintenance of DA fate. Poor in vivo survival is in contrast to work with mouse ES derived DA neurons that showed robust survival in both allo- and xenograft PD models. This suggests that hES cell derived DA neurons exhibit a particular vulnerability that needs to be resolved before the clinical use of these cells can be envisaged. Here we propose to systematically address whether cell or host-based parameters or a combination of the two are responsible for the limited in vivo DA neuron survival and function in rodent and monkey models of PD. These studies should provide the basic foundation for our long-term efforts to translate hES cell based DA neuron differentiation strategies for clinical application. The Study has two major aims: 1. To address whether low numbers of surviving DA neurons in vivo are due to incomplete midbrain DA neuron differentiation in vitro 1.1. Improving patterning of hES derived neural rosettes towards midbrain DA neuron identity 1.2. Timing of patterning in neural rosettes: Early vs. late rosettes as a source of DA neurons. 2. To address whether low numbers of surviving DA neurons in vivo are due to selective cell death of the grafted hES-derived DA neuron population. 2.1. Intrinsic vulnerability of hES derived DA neurons 2.2. Lack of sufficient trophic support in vivo 2.3. Host immunological/inflammatory response interferes with DA neuron survival

描述（由申请人提供）：该提案的目的是确定限制帕金森氏病（PD）临床前模型中人类ES（HES）衍生多巴胺（DA）神经元的体内生存和功能的因素。我们实验室中的初步工作为从HES细胞中衍生的中脑DA神经元提供了高收益方案。然而，在啮齿动物和非人类灵长类动物中，HES细胞衍生的DA神经元的试点移植研究表明，体内生存和维持DA命运的差。较差的体内存活与与小鼠ES衍生的DA神经元的作用相反，这些神经元在同种和异种移植PD模型中均显示出强大的生存。这表明HES细胞得出的DA神经元表现出一种特殊的脆弱性，需要在临床使用这些细胞的临床使用之前就需要解决。在这里，我们建议系统地解决基于细胞的参数或两者的组合是造成PD的啮齿动物和猴子模型中的体内DA神经元存活和功能有限的。这些研究应为我们的长期努力提供基本基础，以翻译基于HES细胞的DA神经元分化策略以进行临床应用。该研究有两个主要目标： 1。解决体内存活的DA神经元数量少，是由于体外中脑DA神经元分化不完全 1.1。改善HES衍生的神经玫瑰花结的模式，向中脑DA神经元身份 1.2。神经玫瑰花结中的图案时间：早期与晚玫瑰花结为DA神经元的来源。 2。解决体内存活的DA神经元数量少，是由于接枝HES衍生的DA神经元种群的选择性细胞死亡。 2.1。 HES衍生的DA神经元的内在脆弱性 2.2。体内缺乏足够的营养支持 2.3。宿主免疫/炎症反应会干扰DA神经元生存