Clear vision requires an optically transparent cornea. Transparency is dependent on corneal hydration, which is controlled by an epithelial cell layer called the corneal endothelium. The endothelium controls hydration by secreting fluid from the corneal stoma to the aqueous humor by ion coupled fluid transport. The membrane and cellular regulatory mechanisms of transport in the endothelium are ot understood. The PI's goal is to develop a model for endothelial fluid transport that includes: the specific membrane transport proteins involved, their polarity of transport, and how transport can be regulated. A long-term goal is to udnerstand how disease, (e.g. fuchs' Endothelial Dystrophy, Diabetes) alters endothelial function. Conceivable, medical therapies can be developed to delay or supplant the need for corneal transplantation in cases of endothelial disease or trauma. Since endothelial transport requires HC03 and Cl, we will examine the mechanisms by which endothelial cells regulate their intracellular pH (pHi), control intracellular (C1) and C1 transport rates, using ion sensitive fluorescent probes for pH, Na+, C1 and Ca2+. Transporter polarity will be determine by: a) physiological measurements on cells grown on permeable filters, b) light and elctron microscope immunocytochemistry and c) western blotting of apical/basolateral membrane fractions. Carbonic anhydrase inhibitors slow endothelial fluid transport. Therefore we will examine the roles of cytoplasmic and membrane bound carbonic anhydrase in HC03 to C02. This will be examined by measuring the effects of HC03 transport and carbonic anhydrase blockers on the unstirred layer pH and fluid transport. Because fluid transport is HC03 dependent, the role of pHi in determining fluid transport will be examined. These studies will provide the basis for future development of medical therapies for restoring the loss of vision that can accompany endothelial disease or trauma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY008834-09
Application #
2882898
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1991-07-01
Project End
2002-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Indiana University Bloomington
Department
Type
Schools of Optometry/Ophthalmol
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
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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