Aquaporins (AQPs) are membrane water channels expressed in many mammalian tissues that carry out fluid transport. Our lab has generated transgenic knockout mice lacking the four AQPs expressed in eye. Utilizing established and novel methods to study eye physiology in mice, we have obtained evidence for the involvement of AQPs in: ocular surface fluid transport, intraocular pressure regulation, cornea and lens transparency, and retinal signal transduction and fluid balance. Our recent work has also implicated the involvement of AQPs in two novel cellular functions: cell migration and proliferation. Follow-up work in this renewal is focused on mechanism-level analysis of these novel AQP functions, and demonstration of proof- of-concept for new clinical therapies for dry eye syndrome, glaucoma, and retinal neovascularization.
Aim 1 will test the involvement of AQP1 in retinal neovascularization. We will determine whether AQP1 deletion/inhibition reduces retinal microvessel proliferation in a mouse model of neonatal hyperoxia followed by normoxia. Biophysical studies will be done to establish the cell-level mechanism of impaired neovascularization in AQP1 deficiency.
Aim 2 will establish the cellular mechanism of AQP3-dependent corneal resurfacing following epithelial cell removal.
Aim 3 will determine the potential utility of CFTR activators in the therapy of dry eye syndrome. These studies will utilize a mouse model of keratoconjunctivitis sicca, and drug efficacy will be assessed using established outcome measures of ocular surface health, as well as novel biophysical measurements of tear film ionic content, osmolality, and volume.
Aim 4 will utilize aquaporin inhibitors, identified by high-throughput screening, as well as AQP1/AQP4 knockout mice, to test whether aquaporin inhibition/knockout can substantially reduce IOP in rodent models of glaucoma, and protect against retinal ganglion cell loss. Together, our studies will establish new roles of aquaporins in the eye with direct implications for new therapies.
|Smith, Alex J; Yao, Xiaoming; Dix, James A et al. (2017) Test of the 'glymphatic' hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. Elife 6:|
|Yao, Xiaoming; Verkman, Alan S (2017) Marked central nervous system pathology in CD59 knockout rats following passive transfer of Neuromyelitis optica immunoglobulin G. Acta Neuropathol Commun 5:15|
|Jin, Byung-Ju; Verkman, A S (2017) Microfluidic platform for rapid measurement of transepithelial water transport. Lab Chip 17:887-895|
|Tradtrantip, Lukmanee; Yao, Xiaoming; Su, Tao et al. (2017) Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica. Acta Neuropathol 134:35-44|
|Yao, Xiaoming; Verkman, Alan S (2017) Complement regulator CD59 prevents peripheral organ injury in rats made seropositive for neuromyelitis optica immunoglobulin G. Acta Neuropathol Commun 5:57|
|Cil, Onur; Phuan, Puay-Wah; Gillespie, Anne Marie et al. (2017) Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor (R)-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins. FASEB J 31:751-760|
|Truong, Eric C; Phuan, Puay W; Reggi, Amanda L et al. (2017) Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A). J Med Chem 60:4626-4635|
|Hirt, Lorenz; Fukuda, Andrew M; Ambadipudi, Kamalakar et al. (2017) Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice. J Cereb Blood Flow Metab 37:277-290|
|Son, Jung-Ho; Zhu, Jie S; Phuan, Puay-Wah et al. (2017) High-Potency Phenylquinoxalinone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activators. J Med Chem 60:2401-2410|
|Tradtrantip, Lukmanee; Jin, Bjung-Ju; Yao, Xiaoming et al. (2017) Aquaporin-Targeted Therapeutics: State-of-the-Field. Adv Exp Med Biol 969:239-250|
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