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The role of NADPH oxidases in Multiple Sclerosis and its animal model, the experimental autoimmune encephalomyelitis

NADPH氧化酶在多发性硬化症及其动物模型、实验性自身免疫性脑脊髓炎中的作用

基本信息

批准号：
276786445
负责人：
Dr. Kerstin Göbel
金额：
--
依托单位：
Klinik für Neurologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/276786445?language=en
关键词：
role NADPH oxidases Multiple Sclerosis

项目摘要

Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, leading to inflammatory lesions with demyelination, axonal degeneration and neuronal loss. As especially neurodegeneration seems to be decisive for irreversible deficits of individuals with chronic inflammatory demyelinating disorders like multiple sclerosis (MS), innovative strategies to prevent neuronal loss are urgently needed. One such high-potential pathway may be the occurrence of reactive oxidative species (ROS) that are known to cause tissue damage and neuronal death in neuroinflammation. However, all major clinical trials to scavenge ROS by applying antioxidant compounds did not result in clinical benefit. One reason for the lack of effect of anti-oxidants might be that their bioavailability is too low in those locations where ROS levels are elevated, as oxidative stress is not a systemic but local phenomenon. On this account, identification and characterization of the disease-relevant enzymatic sources of oxidative stress is urgently needed to allow specific therapeutic targeting of oxidative stress by preventing the formation of ROS in the first place, instead of scavenging ROS in the entire body after they have been formed. Potential sources of ROS are NADPH oxidases (NOX), the only known enzyme family that is especially dedicated to ROS production. Five different isoforms have been identified so far. NOX1, NOX2, NOX4 and NOX5 are expressed in brain, so that these isoforms might be decisive for enhanced inflammation, blood brain barrier breakdown and/or neurodegeneration in neuroinflammation. However, their role, functional impact, the mechanism behind and therefore their participation in terms of CNS autoimmunity in vivo is not yet understood.Therefore, we will assess the functional relevance of NOX in vitro and in vivo. To clarify their role, we will induce an animal model of MS in different NOX-deficient animals in comparison to wildtype controls. To clarify the mode of action, we will analyse different possible pathways and characterize these animals using histological, immunological and molecular biological techniques. After unraveling the mechanism, we will test if the modulation of NOX is effective as therapy in an animal model of MS using different available inhibitors. Finally, we will assess the relevance of NOX also in humans by analyzing blood, cerebrospinal fluid samples and CNS tissue of individuals with MS.In summary, this project offers the unique chance to clarify the functional role and participation of oxidative stress in neuroinflammation and might therefore serve as a future therapeutical strategy to ameliorate inflammatory demyelinating disorders such as MS.

异常的免疫应答代表中枢神经系统（CNS）自身免疫的根本原因，导致具有脱髓鞘、轴突变性和神经元损失的炎性病变。特别是神经变性似乎是决定性的慢性炎症性脱髓鞘疾病如多发性硬化症（MS）的个人的不可逆的赤字，创新的策略，以防止神经元的损失是迫切需要的。一种这样的高潜力途径可能是反应性氧化物质（ROS）的发生，已知其在神经炎症中引起组织损伤和神经元死亡。然而，通过应用抗氧化剂化合物来抑制ROS的所有主要临床试验都没有产生临床益处。抗氧化剂缺乏效果的一个原因可能是它们在ROS水平升高的那些位置的生物利用度太低，因为氧化应激不是全身性的，而是局部的现象。因此，迫切需要对氧化应激的疾病相关酶源进行鉴定和表征，以通过首先防止ROS的形成而不是在整个身体中清除ROS来实现氧化应激的特异性治疗靶向。ROS的潜在来源是NADPH氧化酶（NOX），这是唯一已知的专门用于ROS产生的酶家族。目前已鉴定出5种不同的亚型。NOX 1、NOX 2、NOX 4和NOX 5在脑中表达，因此这些亚型可能是神经炎症中炎症增强、血脑屏障破坏和/或神经变性的决定性因素。然而，他们的作用，功能的影响，背后的机制，因此，他们在CNS自身免疫方面的参与还不清楚。因此，我们将评估NOX在体外和体内的功能相关性。为了阐明它们的作用，我们将在不同的NOX缺陷动物中诱导MS动物模型，并与野生型对照进行比较。为了阐明作用模式，我们将分析不同的可能途径，并使用组织学，免疫学和分子生物学技术表征这些动物。在阐明机制后，我们将测试NOX的调节是否在MS的动物模型中使用不同的可用抑制剂作为治疗有效。最后，我们将通过分析MS患者的血液、脑脊液样本和CNS组织来评估NOX在人类中的相关性。总之，该项目提供了独特的机会来阐明氧化应激在神经炎症中的功能作用和参与，因此可能作为未来的治疗策略来改善炎症性脱髓鞘疾病，如MS。