Stem Cell Therapy and Growth Factor Therapy for ALS

描述（申请人提供）：ALS是一种破坏性疾病，可导致进行性运动神经元变性和死亡。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。尽管其基本的重要性，呼吸功能很少在任何ALS模型中进行研究。在这个修订后的申请中，我们将注意力集中在家族性ALS啮齿动物模型中的呼吸运动功能上，该模型是过表达突变型超氧化物歧化酶-1（SOD 1G 93 A大鼠）的转基因大鼠。指导这一提议的基本假设是，代偿性脊髓神经可塑性抵消了严重的运动神经元变性，保留了呼吸能力，直到疾病进展的晚期。我们建议研究SOD 1G 93 A大鼠脊髓可塑性的代偿机制，并确定是否可以通过增强呼吸可塑性的ghronic治疗（如间歇性低氧暴露）诱导进一步的可塑性。我们还建议调查的贡献，假设在呼吸可塑性或ALS发病机制中发挥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）。为了实现我们的主要目标，将测试四个特定的假设：1）SOD 1G 93 A大鼠利用补偿性脊髓神经可塑性来保持呼吸功能，尽管严重的吸气运动神经元细胞死亡; 2）每日间歇性缺氧增强呼吸可塑性并实际上延迟疾病进展; 3）肌萎缩侧索硬化症期间的补偿性呼吸可塑性的基础是降钙素依赖性BDNF调节; 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变性，从而保持在一个关键的，稳态运动系统的功能。利用各种高度创新的实验方法（例如，体内RNA干扰;和神经祖细胞分泌营养因子的移植），实验室在这一建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拟议的实验将显着推进我们对ALS的理解的可能性。总的来说，这些目标将提供关于家族性ALS进展的独特见解（和其他形式的推断），并可能为未知治愈的神经退行性疾病的新治疗策略提供理论基础。

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.