The complement system in ALS

越来越多的证据表明，中枢神经系统和外周的神经炎症 有助于肌萎缩侧索硬化症的病理生理和疾病进展。此外，临床前和临床研究 补体系统在观察到的ALS神经炎性反应中的作用 缺乏机械性的细节。这项提案的总体目标是调查补体在 补体新方法在ALS小鼠模型中的进展和疾病的病理生理 抑制力。补体抑制将被评估为治疗潜力，同时作为一种 更好地了解补体在肌萎缩侧索硬化症中作用的研究工具。尽管使用补体的临床试验 最近宣布了治疗肌萎缩侧索硬化症的抑制剂，我们将研究的方法提供了巨大的潜力 与进入临床试验的抑制剂相比具有优势。具体目的是考察补语的作用 以及靶向C3抑制对疾病进展和生存的影响，并确定补体- 疾病进展过程中依赖的病理生理学和炎症/免疫特征。预计 产生的数据也将为建立更详细的机械性调查提供基础 开发新的补体抑制治疗方法，可以在优点应用中解决。 目前还没有有效的治疗ALS的方法，我们的治疗策略有可能在多个方面受益。 通过直接保护运动神经元免受中枢补体激活，通过保护运动端- 通过潜在地改变神经胶质细胞-运动神经元之间的相互作用。

Increasing evidence suggests that neuroinflammation in both the central nervous system and periphery contributes to pathophysiology and disease progression of ALS. In addition, both preclinical and clinical studies implicate a role for the complement system in the neuroinflammatory response observed in ALS, although mechanistic details are lacking. The overall goal of this proposal is to investigate the role of complement in the progression and pathophysiology of disease in ALS mouse models using a novel approach of complement inhibition. Complement inhibition will be evaluated for therapeutic potential, while at the same time used as an investigative tool to better understand the role of complement in ALS. Although clinical trials using complement inhibitors to treat ALS have recently been announced, the approach we will investigate offers significant potential advantages over the inhibitors entering clinical trials. The specific aims are to examine the role of complement and the effect of targeted C3 inhibition on disease progression and survival, and to determine complement- dependent pathophysiology and inflammatory/immune profiles during disease progression. It is expected that data generated will provide the foundation on which to build more detailed mechanistic investigations, as well develop novel complement-inhibitory therapeutic approaches that could be addressed in a Merit application. There is no effective treatment for ALS, and our therapeutic strategy has the potential to be beneficial at multiple levels by directly protecting motor neurons from complement activation in the CNS, by protecting motor end- plates, and by potentially modifying glia-motor neuron interactions.