The complement system in ALS

ALS 中的补体系统

基本信息

批准号：
10487640
负责人：
Stephen Tomlinson
金额：
--
依托单位：
RALPH H JOHNSON VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10487640
关键词：
ALS pathology ALS patients Address Aftercare Amyotrophic Lateral Sclerosis Animal Model Animals Area Binding Biological Availability C3bi Central Nervous System Chimeric Proteins Clinical Research Clinical Trials Complement Complement 1q Complement 3d Complement 3d Receptors Complement Activation Complement Inactivators Data Data Set Deposition Deterioration Development Disease Disease Progression Female Foundations Functional disorder Genetic Complementation Test Goals Guidelines Gulf War veteran Human Immune Individual Infection Inflammation Inflammatory Injury Investigation Ligands Methodology Military Personnel Modeling Monoclonal Antibodies Motor Motor Endplate Motor Neurons Mus Neuroglia Pathologic Pathway interactions Peripheral Physiological Pilot Projects Play PrP Predisposition Risk Role Route Safety Site Testing Therapeutic Time Tissues Veterans Work activation product amyotrophic lateral sclerosis therapy analog complement C3d,g complement pathway complement system effective therapy inhibitor interest link protein male mouse model neuroinflammation novel novel strategies novel therapeutic intervention pathogen preclinical study response time use tool

项目摘要

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.

越来越多的证据表明，中枢神经系统和周围神经系统的神经炎症有助于 ALS 的病理生理学和疾病进展。此外，临床前和临床研究暗示补体系统在 ALS 中观察到的神经炎症反应中发挥作用，尽管缺乏机械细节。该提案的总体目标是研究补体在使用补体新方法研究 ALS 小鼠模型中疾病的进展和病理生理学抑制。将评估补体抑制的治疗潜力，同时用作更好地了解补体在 ALS 中的作用的研究工具。尽管临床试验使用补体最近公布了治疗 ALS 的抑制剂，我们将研究的方法具有巨大的潜力与进入临床试验的抑制剂相比具有优势。具体目的是检查补体的作用以及靶向 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。预计生成的数据也将为建立更详细的机制研究奠定基础开发可在优点申请中解决的新型补体抑制治疗方法。 ALS 尚无有效的治疗方法，我们的治疗策略有可能在多个方面有益通过直接保护运动神经元免受中枢神经系统补体激活的影响，通过保护运动末端板，并可能改变神经胶质细胞与运动神经元的相互作用。