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，临床前和临床研究都在ALS中观察到的神经炎症反应中补体系统的作用暗示缺乏机械细节。该提议的总体目标是调查补体在 ALS小鼠模型中疾病的进展和病理生理学使用一种新颖的补体方法抑制。补体抑制作用将用于治疗潜力，同时用作调查工具更好地了解补体在ALS中的作用。尽管使用补充进行临床试验最近宣布了治疗ALS的抑制剂，我们将调查的方法具有巨大的潜力优于进入临床试验的抑制剂的优势。具体目的是检查补充的作用靶向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。预计生成的数据将为建立更详细的机械调查的基础开发新颖的补体抑制性治疗方法，可以在优异应用中解决。 ALS没有有效的治疗方法，我们的治疗策略有可能在多个通过直接保护运动神经元免受中枢神经系统中的补体激活，通过保护电动机端 - 板，并可能通过改变神经胶质神经元相互作用。