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

该项目的最终目标是探索细胞和分子替代策略， 运动神经元变性我们的方法需要全面分析的内在属性， 影响成人肌萎缩侧索硬化症（ALS）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中的运动神经元变性可能不是 细胞自主运动神经元，但也可能部分来自异常的神经胶质环境。因此，在本发明中， 改变神经胶质环境将保护内源性运动神经元，并为运动神经元创造健康的环境。 移植的运动神经元(2)我们已经建立了一个系统来有效地生产健康的人类神经胶质细胞， 如星形胶质细胞，以及来自幼稚胚胎干细胞（ESC）的运动神经元。这些神经细胞 可以代表治疗剂的来源，以及用于解剖神经细胞相互作用的工具， 运动神经元变性(3)人干细胞，包括ESC和神经干细胞/祖细胞，可以是 转基因携带治疗基因。 这个项目将利用我们对间歇性缺氧诱导的 呼吸运动神经元的可塑性在项目1中进行了研究，并建立在运动神经元可塑性的基础上。 ALS发病机制中神经元-星形胶质细胞的相互作用在项目2中评估。我们将对胚胎干细胞进行基因改造 (NIH Registry，WA 01，WA 09）携带细胞死亡抗性基因，移植分化的人 运动神经元进入ALS大鼠的脊髓。通过与项目1和2的互动，我们将评估 是否以及如何间歇性缺氧，呼吸运动，和生长因子产生星形胶质细胞 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 确定一个理想的组合策略，以实现成功移植的人运动神经元在 成人ALS脊髓连同项目1和项目2，我们希望达成一项全面战略， 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.