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

• Applicants: Dr. Kerstin Göbel; Professor Dr. Sven G. Meuth
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 276786445

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.

• DFG Programme: Research Grants