Replacement of Motor Neurons and Astrocytes in ALS Using Human Embryonic Stem Cel

这个项目的最终目标是探索治疗的细胞和分子替代策略。 运动神经元变性。我们的方法需要对内在属性和 影响成人肌萎缩侧索硬化症运动神经元存活的外在因素 脊髓。我们的逻辑基于以下前提：(1)ALS的运动神经元变性可能不是 细胞对运动神经元是自主的，但可能部分来自于异常的神经胶质环境。因此， 改善胶质环境将保护内源性运动神经元，并为 移植的运动神经元。(2)我们已经建立了一套高效生产健康人神经胶质细胞的系统， 例如星形胶质细胞，以及来自幼稚胚胎干细胞(ESCs)的运动神经元。这些神经细胞 可能是治疗剂的来源，也是剖析神经细胞相互作用的工具 运动神经元变性。(3)人类干细胞，包括胚胎干细胞和神经干细胞/祖细胞，可以 通过基因改造来携带治疗基因。 这个项目将利用我们对间歇性低氧诱导的理解的进展。 项目1中的呼吸运动神经元可塑性研究，并建立在运动的基础上 在项目2中评估了ALS发病中神经元-星形胶质细胞的相互作用。我们将对hESCs进行基因修饰 (NIH注册，WA01，WA09)携带细胞抗死亡基因并移植分化的人 肌萎缩侧索硬化症大鼠脊髓的运动神经元。通过与项目1和2的互动，我们将评估 间歇性低氧、呼吸运动和产生生长因子的星形胶质细胞是否以及如何 促进移植的人运动神经元的存活、整合和轴突生长。我们的目标是 确定一种理想的组合策略以实现成功的人运动神经元移植 成人肌萎缩侧索硬化症脊髓。与项目1和项目2一起，我们希望达成一项全面的战略， 治疗毁灭性的肌萎缩侧索硬化症。

The ultimate goal of this project is to explore cellular and molecular replacement strategies for treating motor neuron degeneration. Our approach entails comprehensive analyses of both intrinsic properties and extrinsic factors that affect the survival of human motor neurons in adult almyotrophic lateral sclerosis (ALS) spinal cord. Our logic is based on the following premises: (1) Motor neuron degeneration in ALS may not be cell autonomous to motor neurons but may arise, in part, from an abnormal glial environment. Thus, modifying the glial environment will protect endogenous motor neurons and create a healthy milieu for grafted motor neurons. (2) We have established a system to efficiently produce healthy human glial cells, such as astrocytes, as well as motor neurons from naive embryonic stem cells (ESCs). These neural cells may represent a source of therapeutic agents, as well as a tool for dissecting neural cell interactions during motor neuron degeneration. (3) Human stem cells, including ESCs and neural stem/progenitor cells, can be genetically modified to carry therapeutic genes. This project will take advantage of advances in our understanding of intermittent hypoxia-induced respiratory motor neuron plasticity under investigation in Project 1, and build upon the foundation of motor neuron-astrocyte interactions in ALS pathogenesis assessed in Project 2. We will genetically modify hESCs (NIH Registry, WA01, WA09) to carry cell death-resistant genes and transplant the differentiated human motor neurons into the spinal cord of ALS rats. Through interactions with projects 1 & 2, we will evaluate whether and how intermittent hypoxia, a respiratory exercise, and growth factor-producing astrocytes promote the survival, integration, and axonal growth of the grafted human motor neurons. Our goal is to identify an ideal combinatory strategy to achieve successful transplantation of human motor neurons in the adult ALS spinal cord. Together with projects 1 & 2, we hope to arrive at a comprehensive strategy for treating the devastating ALS.