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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08NS078555-01A1
Application #
8509867
Study Section
NST-2 Subcommittee (NST)
Program Officer
Utz, Ursula
Project Start
2013-05-01
Project End
2018-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$193,023
Indirect Cost
$14,298
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Pekcevik, Yeliz; Mitchell, Charles H; Mealy, Maureen A et al. (2016) Differentiating neuromyelitis optica from other causes of longitudinally extensive transverse myelitis on spinal magnetic resonance imaging. Mult Scler 22:302-11
Kessler, Remi A; Mealy, Maureen A; Levy, Michael (2016) Treatment of Neuromyelitis Optica Spectrum Disorder: Acute, Preventive, and Symptomatic. Curr Treat Options Neurol 18:2
Juryńczyk, Maciej; Weinshenker, Brian; Akman-Demir, Gulsen et al. (2016) Status of diagnostic approaches to AQP4-IgG seronegative NMO and NMO/MS overlap syndromes. J Neurol 263:140-9
Levy, Michael; Boulis, Nicholas; Rao, Mahendra et al. (2016) Regenerative cellular therapies for neurologic diseases. Brain Res 1638:88-96
Pekcevik, Yeliz; Orman, Gunes; Lee, In Ho et al. (2016) What do we know about brain contrast enhancement patterns in neuromyelitis optica? Clin Imaging 40:573-80
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
Kremer, Stephane; Renard, Felix; Achard, Sophie et al. (2015) Use of Advanced Magnetic Resonance Imaging Techniques in Neuromyelitis Optica Spectrum Disorder. JAMA Neurol 72:815-22
Bennett, J L; de Seze, J; Lana-Peixoto, M et al. (2015) Neuromyelitis optica and multiple sclerosis: Seeing differences through optical coherence tomography. Mult Scler 21:678-88
Mealy, Maureen A; Levy, Michael (2015) Favorable outcome of granulocyte colony-stimulating factor use in neuromyelitis optica patients presenting with agranulocytosis in the setting of rituximab. J Neuroimmunol 287:29-30
Weinshenker, Brian G; Barron, Gerard; Behne, Jacinta M et al. (2015) Challenges and opportunities in designing clinical trials for neuromyelitis optica. Neurology 84:1805-15

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