Aquaporins (AQPs) are water transporting proteins expressed widely in mammalian tissues including the eye. Aquaporin-4 (AQP4) is expressed in astrocytes throughout the central nervous system, including optic nerve and retina. This renewal application is focused on the AQP4 disease neuromyelitis optica (NMO), an autoimmune, inflammatory demyelinating disease primarily affecting optic nerve and spinal cord, producing optic neuritis and blindness. A defining feature of NMO is the presence of serum autoantibodies (NMO-IgG) against AQP4. The proposed research will investigate basic cellular and molecular questions in NMO (Aim 1), NMO disease pathogenesis mechanisms (Aim 2), and a new NMO therapy (Aim 3).
Aim 1 will characterize the interaction of NMO-IgG with AQP4. Utilizing novel biophysical and biochemical tools effects of NMO-IgG on AQP4 function, assembly and cellular processing will be investigated, as well as downstream cytotoxicity. The hypothesis will be tested that AQP4 assembly in OAPs is crucial in NMO pathogenesis, and hence a target for therapy.
Aim 2 will elucidate the mechanisms of ocular pathogenesis in NMO caused by NMO-IgG. Ex vivo (optic nerve culture) and in vivo mouse models of NMO optic neuritis will be used, as well as an engineered NMO 'super-antibody', to test the hypothesis that NMO-IgG binding to AQP4 causes complement-dependent astrocyte cytotoxicity, leukocyte recruitment and inflammation, leading to demyelination. The role of granulocytes, macrophages and NK cells will be investigated, with the goal of defining new therapeutic targets.
Aim 3 will advance a new therapy of optic neuritis in NMO in which blocking of NMO-IgG binding to AQP4, the initiating pathogenic event in NMO, reduces NMO pathology. We have developed both monoclonal antibody and small-molecule approaches, which will be optimized and used in mouse models to obtain proof-of-concept that blocking NMO-IgG binding to AQP4 can reduce ocular pathology in NMO.

Public Health Relevance

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system caused by autoantibodies against water channel aquaporin-4. The goal of this proposal is to understand how NMO autoantibodies cause optic neuritis and blindness, and to develop new therapies for NMO.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
Zip Code
Esteva-Font, Cristina; Jin, Byung-Ju; Lee, Sujin et al. (2016) Experimental Evaluation of Proposed Small-Molecule Inhibitors of Water Channel Aquaporin-1. Mol Pharmacol 89:686-93
Yao, Xiaoming; Su, Tao; Verkman, A S (2016) Clobetasol promotes remyelination in a mouse model of neuromyelitis optica. Acta Neuropathol Commun 4:42
Felix, Christian M; Levin, Marc H; Verkman, Alan S (2016) Complement-independent retinal pathology produced by intravitreal injection of neuromyelitis optica immunoglobulin G. J Neuroinflammation 13:275
Flores, Alyssa M; Casey, Scott D; Felix, Christian M et al. (2016) Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease. FASEB J 30:1789-97
Cil, Onur; Haggie, Peter M; Phuan, Puay-Wah et al. (2016) Small-Molecule Inhibitors of Pendrin Potentiate the Diuretic Action of Furosemide. J Am Soc Nephrol 27:3706-3714
Hirt, Lorenz; Fukuda, Andrew M; Ambadipudi, Kamalakar et al. (2016) Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice. J Cereb Blood Flow Metab :
Jin, Byung-Ju; Smith, Alex J; Verkman, Alan S (2016) Spatial model of convective solute transport in brain extracellular space does not support a ""glymphatic"" mechanism. J Gen Physiol 148:489-501
Cil, Onur; Phuan, Puay-Wah; Lee, Sujin et al. (2016) CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation. Cell Mol Gastroenterol Hepatol 2:317-327
Zhang, Hua; Verkman, A S (2015) Aquaporin-1 water permeability as a novel determinant of axonal regeneration in dorsal root ganglion neurons. Exp Neurol 265:152-9
Cil, Onur; Esteva-Font, Cristina; Tas, Sadik Taskin et al. (2015) Salt-sparing diuretic action of a water-soluble urea analog inhibitor of urea transporters UT-A and UT-B in rats. Kidney Int 88:311-20

Showing the most recent 10 out of 231 publications