Stem Cell Therapy and Growth Factor Therapy for ALS

描述（由申请人提供）：肌萎缩性侧索硬化症是一种毁灭性疾病，可导致进行性运动神经元退化和死亡。大多数ALS患者发展为严重的呼吸功能不全，最终死于呼吸衰竭。尽管呼吸功能具有重要的基础意义，但在ALS模型中很少有研究。在这篇修订后的申请中，我们将重点关注家族性ALS啮齿动物模型的呼吸运动功能，即转基因大鼠过表达突变的超氧化物歧化酶-1 （SOD1G93A大鼠）。指导这一建议的基本假设是代偿性脊髓神经可塑性抵消了严重的运动神经元退化，保留了呼吸能力，直到疾病进展的后期。我们建议研究SOD1G93A大鼠代偿性脊柱可塑性的机制，并确定是否可以通过增强呼吸可塑性的慢性治疗（如间歇性低氧暴露）诱导进一步的可塑性。我们还建议研究在呼吸可塑性或ALS发病机制中起关键作用的关键营养因子：脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF）的贡献。为了实现我们的主要目标，我们将测试四个特定的假设：1)SOD1G93A大鼠利用代偿性脊髓神经可塑性来维持呼吸功能，尽管吸气运动神经元细胞严重死亡；2)每日间歇性缺氧增强呼吸可塑性，实际上延缓疾病进展；3) 5 -羟色胺依赖性BDNF调节是ALS患者代偿性呼吸可塑性的基础；4) VEGF改善呼吸运动输出和运动神经元存活。我们的观点是独特的，专注于补偿机制，抵消进行性运动神经元退化，从而保持功能在一个关键的，稳态运动系统。利用多样化和高度创新的实验方法（例如，体内RNA干扰；和分泌营养因子的神经祖细胞移植），实验室在该提议的各个方面的丰富经验，以及令人兴奋的初步数据，增加了提议的实验将显著推进我们对ALS的理解的可能性。总的来说，这些目标将为家族性肌萎缩侧索硬化症（以及其他形式的推断）的进展提供独特的见解，并可能为尚无已知治愈方法的神经退行性疾病的新治疗策略提供依据。

Description (provided by applicant): ALS is a devastating disease causing progressive motor neuron degeneration and death. Most ALS patients develop severe respiratory insufficiency and, ultimately, die from ventilatory failure. Despite its fundamental mportance, respiratory function has seldom been studied in any ALS model. In this revised application, we focus attention on respiratory motor function in a rodent model of familial ALS, the transgenic rat overexpressing mutated superoxide dismutase-1 (SOD1G93A rat). The fundamental hypothesis guiding this proposal is that compensatory spinal neuroplasticity offsets severe motor neuron degeneration, preserving the ability to breathe until late in disease progression. We propose to investigate mechanisms of compensatory spinal plasticity in SOD1G93A rats, and to determine if further plasticity can be induced with ghronic treatments that enhance respiratory plasticity, such as intermittent exposures to low oxygen (hypoxia). We also propose to investigate the contributions of key trophic factors postulated to play key roles in respiratory plasticity or ALS pathogenesis: brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). To achieve our primary goal, four specific hypotheses will be tested: 1) SOD1G93A rats utilize compensatory spinal neuroplasticity to preserve ventilatory function despite severe inspiratory motor neuron cell death; 2) daily intermittent hypoxia enhances respiratory plasticity and actually delays disease progression; 3) serotonin-dependent BDNF regulation underlies compensatory respiratory plasticity during ALS; and 4) VEGF improves respiratory motor output and motor neuron survival. Our perspective is unique, focusing on compensatory mechanisms that offset progressive motor neuron degeneration, thereby preserving function in a critical, homeostatic motor system. The utilization of diverse and highly innovative experimental approaches (e.g., RNA interference in vivo; and transplantation of neural progenitor cells secreting trophic factors), the extensive experience of the laboratory with all aspects of this proposal, and exciting preliminary data increase the likelihood that the proposed experiments will significantly advance our understanding of ALS. Collectively, these aims will provide unique insights concerning the progression of familial ALS (and other forms by inference), and may provide the rationale for novel therapeutic strategies for a neurodegenerative disease with no known cure.