This is a proposal for a 5-year K08 Mentored Clinical Scientist Research Career Development Award from the National Institutes of Neurological Disease and Stroke (NINDS) to investigate the role of NMO-IgG and Aquaporin-4 specific T cells in the immunopathogenesis of neuromyelitis optical. Neuromyelitis optical (NMO) is a devastating neuroinflammatory disorder targeting the optic nerves and spinal cord leading to blindness and paralysis. NMO is associated with a serologic biomarker, the NMO-IgG, which targets the aquaporin-4 (AQP4) water channel on the end feet of astrocytes in the central nervous system. This grant is designed to elucidate the immunopathogenesis of neuromyelitis optical focusing on three aspects: 1. Characterizing the role of the NMO-IgG in inducing or exacerbating the NMO disease phenotype by recruiting granulocytes, 2. Identifying the target of the NMO-IgG on AQP4 in the spinal cord and optic nerves using specific anti-AQP4 antibodies, 3. Evaluating the role of Th17 cells specific for AQP4 in instigating and facilitating inflammation in the central nervous system.
Each aim i s complimentary to the whole project and will provide unique insights into the pathogenesis of NMO. The principle investigator for this project is Michael Levy, MD, PhD, and an Assistant Professor in the Department of Neurology at the Johns Hopkins University who is working under the mentorship of Peter Calabresi, MD, Professor and Director of the Division of Neuroimmunology at Johns Hopkins University. Dr. Calabresi is a leader in the clinical and research fields of multiple sclerosis and neuroimmunologic diseases. Together in one of the nation's most productive research environments, Dr. Levy will have 75% protected time to spend in the lab and use the rest of the time to translate his basic science work to the bedside in the NMO clinic and on the inpatient neurology service at Johns Hopkins Hospital.

Public Health Relevance

Neuromyelitis optical (NMO) is a devastating neurologic disease that that tends to afflict young women, especially of African American ethnicity. As the incidence of NMO continues to grow, work on the basic science and translational aspects of NMO is becoming increasingly important for the mission of the National Institute of Neurological Disorders and Stroke to reduce the burden of neurological disease by every age group, by every segment of society, by people all over the world. While this project focuses on aquaporin-4 in NMO, the results may impact research in other CNS inflammatory disorders that involve aquaporin's and the blood brain barrier, such as transverse myelitis and multiple sclerosis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Study Section
NST-2 Subcommittee (NST)
Program Officer
Utz, Ursula
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Johns Hopkins University
Schools of Medicine
United States
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Mealy, Maureen A; Kim, Su-Hyun; Schmidt, Felix et al. (2018) Aquaporin-4 serostatus does not predict response to immunotherapy in neuromyelitis optica spectrum disorders. Mult Scler 24:1737-1742
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Sagan, Sharon A; Winger, Ryan C; Cruz-Herranz, Andrés et al. (2016) Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4. Proc Natl Acad Sci U S A 113:14781-14786
Abboud, Hesham; Petrak, Alex; Mealy, Maureen et al. (2016) Treatment of acute relapses in neuromyelitis optica: Steroids alone versus steroids plus plasma exchange. Mult Scler 22:185-92

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