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

• 批准号: 7561098
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7561098
• 关键词: Address; Allografting; Cell Death; Cells; Clinical; Derivation procedure; Disease model; Dopamine; Exhibits; Foundations; Goals; Human; In Vitro; Inflammatory Response; Maintenance; Midbrain structure; Modeling; Monkeys; Mus; Parkinson Disease; Pattern; Population; Pre-Clinical Model; Protocols documentation; Rodent; Source; Time; Translating; Transplantation; Work; Xenograft procedure; base; clinical application; dopaminergic neuron; human embryonic stem cell; improved; in vivo; nerve stem cell; nonhuman primate; relating to nervous system

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）：该提案的目标是确定在帕金森病（PD）临床前模型中限制人ES（hES）衍生多巴胺（DA）神经元体内存活和功能的因素。我们实验室的初步工作为从hES细胞中获得中脑DA神经元提供了高产量的方案。然而，在啮齿动物和非人灵长类动物中的hES细胞衍生的DA神经元的初步移植研究表明DA命运的体内存活和维持较差。较差的体内存活与小鼠ES衍生的DA神经元的工作形成对比，所述DA神经元在同种异体和异种移植PD模型中均显示出稳健的存活。这表明hES细胞衍生的DA神经元表现出特殊的脆弱性，在设想这些细胞的临床应用之前需要解决这个问题。在这里，我们建议系统地解决是否细胞或主机为基础的参数或两者的组合是负责有限的体内DA神经元的存活和功能在啮齿动物和猴子模型的PD。这些研究将为我们长期致力于将基于hES细胞的DA神经元分化策略转化为临床应用提供基础。这项研究有两个主要目的： 1.探讨体内存活的DA神经元数量少是否是由于体外中脑DA神经元分化不完全所致 1.1.改善hES衍生的神经元对中脑DA神经元身份的模式化 1.2.在神经rod模式的时间：早期与晚期rod作为DA神经元的来源。 2.为了解决体内存活的DA神经元的低数量是否是由于移植的hES衍生的DA神经元群体的选择性细胞死亡。 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/炎症反应干扰DA神经元存活