The goal of this study is to understand how the corneal endothelial fluid """"""""pump"""""""" works. The """"""""pump"""""""" maintains corneal hydration and transparency. When the """"""""pump"""""""" fails due to trauma, inflammation, ageing, or corneal dystrophy, corneal edema ensues, transparency is lost and vision is significantly degraded. The usual therapy is transplantation, which is not without significant compromises and complications. Knowing how the """"""""pump"""""""" works is one approach to developing medical therapies that could delay or supplant the need for transplantation. As the population ages and the prevalence of endothelial dysfunction increases, demand for endothelial therapy will also increase. Ion transport is a key feature of the """"""""pump"""""""". Up to now the """"""""pump"""""""" has been modeled as a classic ion secretory mechanism that is bicarbonate dependent and carbonic anhydrase sensitive. Previous studies and our work in the preceding period however, indicate that alternate models need to be investigated. Our overall hypothesis is that the corneal endothelium is a lactate removal """"""""pump"""""""". Because the cornea is very glycolytic and must remove the end product, which is lactic acid, we propose that the transcellular flux of lactate is coupled to water movement;that lactate flux is via monocarboxylic acid transporters (MCTs);and that the buffering action of HCO3-, CA activity, membrane pHi regulators &HCO3- transporters act in concert to facilitate the flux of lactate. By buffering the protons transported by the MCTs, lactate:H+ &water flux is maximized by preventing reductions in the driving force for continued lactate:H+ transport. Using multiple in vitro &in vivo complementary approaches this will be tested in three aims.
Aim 1 will investigate the role of buffering capacity on water and lactate fluxes. The flux ratio, i.e. mMoles lactate/ul water can be estimated to determine the tonicity of this osmotic coupling. If water coupled to lactate is significant, we expect isotonic (300 mEq/L) transport.
Aim 2 will investigate the role of primary and secondary active transport (Na+,K+ ATPase,1Na+:2HCO3- cotransport, and Na+/H+ exchange) in facilitating lactate flux across the endothelium by determining the change in lactate flux ratio when these transporters are disturbed.
Aim 3 will investigate the role of MCTs in facilitated lactate transport. Using pharmacological inhibitors and shRNA approaches in vivo we predict that inhibition of MCTs will have significant effects on corneal hydration. If the hypothesis is correct, we will have a more complete model of endothelial function that will allow further development of diagnostic and medical therapies or engineering of endothelial-like cells with the requisite transport properties.
The goal of this study is to understand how the corneal endothelial fluid pump works to keep the cornea transparent. Experiments are designed to test the hypothesis that the endothelium transports water from stroma to anterior chamber by facilitating the flux of lactic acid.
|Bhadange, Yogesh; Lautert, Jeferson; Li, Shimin et al. (2018) Hypoxia and the Prolyl Hydroxylase Inhibitor FG-4592 Protect Corneal Endothelial Cells From Mechanical and Perioperative Surgical Stress. Cornea 37:501-507|
|Li, Shimin; Hundal, Karmjot Singh; Chen, Xingjuan et al. (2018) R125H, W240S, C386R, and V507I SLC4A11 mutations associated with corneal endothelial dystrophy affect the transporter function but not trafficking in PS120 cells. Exp Eye Res 180:86-91|
|Zhang, Wenlin; Ogando, Diego G; Kim, Edward T et al. (2017) Conditionally Immortal Slc4a11-/- Mouse Corneal Endothelial Cell Line Recapitulates Disrupted Glutaminolysis Seen in Slc4a11-/- Mouse Model. Invest Ophthalmol Vis Sci 58:3723-3731|
|Zhang, Wenlin; Li, Hongde; Ogando, Diego G et al. (2017) Glutaminolysis is Essential for Energy Production and Ion Transport in Human Corneal Endothelium. EBioMedicine 16:292-301|
|Li, Shimin; Kim, Edward; Bonanno, Joseph A (2016) Fluid transport by the cornea endothelium is dependent on buffering lactic acid efflux. Am J Physiol Cell Physiol 311:C116-26|
|Zhang, Wenlin; Ogando, Diego G; Bonanno, Joseph A et al. (2015) Human SLC4A11 Is a Novel NH3/H+ Co-transporter. J Biol Chem 290:16894-905|
|Li, Shimin; Nguyen, Tracy T; Bonanno, Joseph A (2014) CD147 required for corneal endothelial lactate transport. Invest Ophthalmol Vis Sci 55:4673-81|
|Robertson, Danielle M; Alexander, Larry J; Bonanno, Joseph A et al. (2014) Cornea and ocular surface disease: application of cutting-edge optometric research. Optom Vis Sci 91:S3-16|
|Jalimarada, Supriya S; Ogando, Diego G; Bonanno, Joseph A (2014) Loss of ion transporters and increased unfolded protein response in Fuchs' dystrophy. Mol Vis 20:1668-79|
|Jalimarada, Supriya S; Ogando, Diego G; Vithana, Eranga N et al. (2013) Ion transport function of SLC4A11 in corneal endothelium. Invest Ophthalmol Vis Sci 54:4330-40|
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