Stem Cell Therapy for Motor Neuron Disease

描述(申请人提供)：肌萎缩侧索硬化症(ALS)是一种致命的成人起病的神经系统疾病，其特征是涉及运动神经元的退化。目前还没有有效的治疗方法来显著延缓这种疾病的发展，或扭转这种毁灭性和致命的残疾。使用干细胞，尤其是星形胶质细胞，似乎代表了治疗神经退行性疾病的一种新方法：基于干细胞的策略可以重新启动发育过程，将新细胞无缝地插入退化的环境中，而不是直接对抗病理过程。最近的研究证明，在各种神经系统损伤中，某些干细胞具有促进神经保护/恢复的潜力。这项提案的总体目标将是研究小鼠星形胶质干细胞移植作为治疗动物模型ALS的一种治疗方式的潜力。在ALS患者和动物模型中，星形胶质细胞谷氨酸转运体GLT-1/EAAT2缺陷导致兴奋性神经变性。初步研究证明，谷氨酸运输的替代可以有效和显著地减缓疾病；而使用选定的营养因子可以促进运动轴突生长，还可以保护运动神经元。胶质细胞限制性前体细胞似乎能够(在体外)移植到脊髓外植体中，表达潜在的神经保护作用的星形胶质GLT-1/EAAT2谷氨酸转运体，并有效地保护谷氨酸介导的神经元死亡。这项建议的总体目标是：1)在体外和植入后表征神经胶质前体细胞谷氨酸转运体亚型的正常调节；2)利用体外模型建立神经胶质前体干细胞的神经保护作用。为了严格评估谷氨酸转运体相对于GRP的其他特性(例如，营养因子释放)的作用，我们将进行以下研究：1)将谷氨酸转运体与转运体缺失小鼠(GLT-1，GLAST，GLT-1/GLAST)制备的GRP进行比较；3)在ALS-G93A SOD1突变小鼠和大鼠的转基因动物模型中，通过检测干细胞分化和神经保护来确定胶质前体细胞是否能抵御慢性神经元损伤。总而言之，这些研究将提供有关星形胶质干细胞在ALS相关的急、慢性损伤模型中改变神经变性的效用的数据，并有望提供重要的临床前信息。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a fatal adult onset neurological disorder that characteristically involve the degeneration of motor neurons. No effective treatment exists to substantially retard the progression of this disease, or to reverse the devastating and fatal disability. The use of stem cells in general and astroglial in particular, appears to represent a new approach to the treatment of neurodegenerative disease: rather than directly combating a pathological process, stem cell-based strategies could reinvoke developmental processes to insert new cells seamlessly into the degenerated environment. Recent studies document the potential of certain stem cells in promoting neuroprotection/recovery in a variety of nervous system injuries. The overall goal of this proposal will be to study the potential of murine astroglial stem cell transplantation as a therapeutic modality for the treatment of animal models ALS. In ALS patients and in animal models, defects in astroglial glutamate transporter GLT-1/EAAT2 lead to excitotoxic neural degeneration. Preliminary studies document that replacement of glutamate transport can effectively and dramatically slow down the disease; while use of selected trophic factors can enhance motor axon growth and also protect motor neurons. Glial-restricted progenitor cells appear to be able to engraft into spinal cord explants (in vitro), express the potentially neuroprotective astroglial GLT-1/EAAT2 glutamate transporter, and potently protect against glutamate-mediated neuronal death. The overall goal of this proposal will be to: 1) Characterize the normal regulation of glutamate transporter subtypes in glial progenitor cells in vitro and after engraftment; 2) Establish the neuroprotection by glial progenitor stem cells using in vitro models. To critically evaluate the role of glutamate transporter versus other properties of GRP (e.g. trophic factor release) we will perform comparisons with GRPs prepared from transporter null mice (GLT-1, GLAST, GLT-1/GLAST); 3) Determine if glial progenitor cells can protect against chronic neuronal injury by examining stem cell differentiation and neuroprotection in vivo in a transgenic animal model of ALS - G93A SOD 1 mutant mice and rats. Over all, these studies will provide data on the utility of astroglial stem cells to alter neurodegeneration in acute and chronic injury models relevant to ALS and hopefully provide important critical pre-clinical information.