Models of Motor Neuron Disease: Stem Cell Therapies

运动神经元疾病模型：干细胞疗法

• 批准号: 6680449
• 负责人: VASSILIS E. KOLIATSOS
• 金额: $ 34.95万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6680449
• 关键词: axon; cell death; cell differentiation; degenerative motor system disease; disease /disorder model; electron microscopy; genetically modified animals; glia; histochemistry /cytochemistry; laboratory mouse; laboratory rat; motor neurons; nerve stem cell; neural degeneration; neurons; nonhuman therapy evaluation; synapses

DESCRIPTION (provided by applicant): Motor neuron diseases, including ALS and SMA, are featured by degeneration and death of lower motor neurons. Significant progress in genetics has allowed for the construction of spectacular transgenic models, but the basic pathogenic mechanisms of these illnesses remain unknown and there are no disease-modifying treatments. Cell death prevention strategies, including the use of trophic factors and small neuroprotective molecules, have had very limited clinical success. Perhaps the greatest promise lies in cell replacement strategies, based on our preliminary findings that exogenous neural stem cells (NSCs) can become avidly engrafted in the adult rat spinal cord and give rise to cells with clinically relevant phenotypes, i.e. neurons and ensheathing cells. Encouraged by these findings, we propose a stepwise approach to ensure that rodent and human NSCs differentiate into neurons and glia when transplanted at the sites of degenerated motor neurons in rat spinal cord after excitotoxic applications and in the ventral horn of transgenic animals which show the clinical features of ALS, i.e. SOD1 transgenic rodents. We are interested in the ability of NSC-derived neurons, suggested by our preliminary findings, to receive excitatory and inhibitory innervation and extend axons to ventral roots towards muscle targets. We expect that the restitution of the degenerating neuromuscular units will improve muscle strength in SOD1 transgenic animals, as assessed by behavioral testing on motorized devices. In concert, we propose to examine the essential preclinical parameters for the consideration of NSCs as therapeutic tools for motor neuron disease.

描述（由申请人提供）：较低运动神经元的退化和死亡，包括ALS和SMA在内的运动神经元疾病。遗传学方面的重大进展允许构建壮观的转基因模型，但是这些疾病的基本致病机制仍然未知，并且没有疾病调整的治疗方法。细胞死亡预防策略，包括使用营养因子和小型神经保护分子，其临床成功非常有限。基于我们的初步发现，即外源性神经干细胞（NSC）可能会热衷于成年大鼠脊髓，并引起具有临床相关表型的细胞，即神经元和振兴细胞。在这些发现的鼓励下，我们提出了一种逐步方法，以确保在兴​​奋性毒性应用后在大鼠脊髓中退化的运动神经元的部位以及转基因动物的腹角中移植时，将啮齿动物和人类NSC分化为神经元和神经胶质。我们对NSC衍生的神经元的能力感兴趣，该神经元的初步发现提出，接受兴奋性和抑制性神经，并将轴突扩展到腹部根部向肌肉靶标。我们预计，通过在电动装置上的行为测试来评估，退化的神经肌肉单元将改善SOD1转基因动物的肌肉力量。在协同的过程中，我们建议研究将NSC作为运动神经元疾病的治疗工具的基本临床前参数。