Investigating the Action and Physiological Role of SLC4A11 in the Cornea

Investigating the Action and Physiological Role of SLC4A11 in the Cornea is sponsored by National Eye Institute (NEI), NIH. This renewed grant focuses on the study of endothelial membrane transport proteins in the cornea, specifically SLC4A11, and its role in acid-base balance for the corneal fluid pump using mouse models of corneal disease like Fuchs' endothelial corneal dystrophy (FECD).

Investigating the Action and Physiological Role of Slc4a11 in the Cornea - Mark Parker Investigating the Action and Physiological Role of Slc4a11 in the Cornea State University of New York at Buffalo, Amherst, NY, United States Search grants from State University of New York at Buffalo Targeting Novel BMPR2 modifiers in Pulmonary Hypertension with Repurposed Drugs Genetic Basis Of Cortical Malfunction In Schizophrenia Metallothionein in Reproduction and Development The Molecular Structure of Nucleic Acids Studies on the Origin of Pandemic Influenza Viruses Teamwork, Targets, Technology, and Tight Control in Newly Diagnosed Pediatric T1D: 4T Study Mechanistically based therapeutic strategies in murine primary biliary cholangitis Use of Continuous Glucose Monitoring (CGM) in End-Stage Renal Disease (ESRD) Patients with Type 2 Diabetes Pilot Study of the Nutrition-Enhanced Wellness for Diabetes Self-Management Program (NEW-DSMP) among Low-Income Adults with Type II Diabetes Combining experiments of man and nature to target human insulin resistance Vision loss associated with corneal clouding affects ~300,000 individuals in the United States.

The thickest layer of the cornea is the stroma; a transparent collagen matrix that tends to draw fluid from the aqueous humor. A layer of corneal endothelial cells between the stroma and aqueous humor provides little physical barrier to this fluid movement but actively extrudes osmolytes (bicarbonate lactate), and thus fluid, from the stroma back into the aqueous humor.

Endothelial dysfunction allows fluid to accumulate in the stroma, distorting the matrix and causing it to scatter light. Corneal transplant has remained the definitive treatment for all corneal diseases for over a century, but advances our in our understanding of the genetics of disease and mechanisms of endothelial function have paved the way for development of bioengineered corneas and less invasive treatments.

However, we still do not have a complete understanding of how the endothelium works. It is only relatively recently that genetic-linkage studies revealed the critical importance of the membrane transport protein SLC4A11 to endothelial health. We have recently established that SLC4A11 is a pH-sensitive H+ conductor.

We hypothesize that SLC4A11 acts as a master regulator of endothelial cell pH, sensing and countering pH disturbance in the vicinity of pH-sensitive osmolyte transporters NBCe1-B (Na+/2HCO ? cotransporter) and MCT1 (H+/lactate? 3 cotransporter).

In the first part of our proposal we express SLC4A11 in Xenopus oocytes and, using a combination of ion-selective microelectrodes and voltage-clamp circuitry in order to determine the kinetic parameters governing SLC4A11 action that are necessary to implement SLC4A11 in mathematical models of endothelial fluid transport. We also examine the influence of SLC4A11 on NBCe1-B and MCT1 action.

In the second part of our proposal we compare the progression of corneal disease signs in Slc4a11-knockout mice and our novel Nbce1b-knockout mouse to study the long-term effects of disturbed endothelial fluid transport. Finally, we investigate a novel therapeutic strategy to de-swell the edematous corneas of Slc4a11-knockout mice using eye drops.

The long term goal of our research program is to understand how endothelial cells perform and balance fluid transport with pH homeostasis and to understand the importance of SLC4A11 to corneal health and disease. This project is aligned with the mission of the Corneal Disease Program of the NEI, to apply knowledge from basic science discoveries to the understanding of the physiology of the cornea and to the treatment of corneal disease.

The cornea is the transparent, outermost layer of the eye. Disease can cause the cornea to become cloudy, resulting in vision loss. We aim to understand how the membrane-transport proteins SLC4A11 and SLC4A4 help to maintain corneal transparency and why SLC4A11 and SLC4A4 mutations cause vision loss.

Agency National Institute of Health (NIH) Institute National Eye Institute (NEI) Type Research Project (R01) Project # 1R01EY028580-01 Study Section Special Emphasis Panel (ZRG1) Program Officer Mckie, George Ann Name State University of New York at Buffalo Investigating the Action and Physiological Role of Slc4a11 in the Cornea Parker, Mark / State University of New York at Buffalo Investigating the Action and Physiological Role of Slc4a11 in the Cornea Parker, Mark / State University of New York at Buffalo Investigating the Action and Physiological Role of Slc4a11 in the Cornea Parker, Mark / State University of New York at Buffalo Investigating the Action and Physiological Role of Slc4a11 in the Cornea Parker, Mark / State University of New York at Buffalo Parker, Mark D (2018) Mouse models of SLC4-linked disorders of HCO3--transporter dysfunction.

Am J Physiol Cell Physiol 314:C569-C588 Be the first to comment on Mark Parker's grant