NIH Renews Parker’s Funding to Study Corneal Diseases

By Dirk Hoffman

The National Eye Institute is funding a five-year $1.95 million grant titled “Investigating the Action and Physiological Role of SLC4A11 in the Cornea.”

The research focuses on the study of endothelial membrane transport proteins in the cornea, according to Parker, the grant’s principal investigator.

The corneal endothelium is a layer of cells at the back of the cornea that pumps fluid out of the cornea to keep it transparent. Diseases of the endothelium can cause the cornea to become swollen and cloudy, resulting in vision loss, Parker states.

“This is a renewal of a previous grant to continue our research into the importance of acid-base balance for the corneal fluid pump, using mouse models of corneal disease,” he says.

“In the previous funding period, we focused on the characterization of a corneal proton-channel (SLC4A11) which causes corneal swelling and vision loss from birth when mutated in humans and mice.”

As part of those studies, the researchers generated a new mouse model which carries a different type of mutation in its SLC4A11 gene; one that is associated with progressive, rather than congenital, vision loss.

“This disease is called Fuchs’ endothelial corneal dystrophy (FECD) and starts to manifest at 50+ years in affected patients.” Parker says. “It is study of this new mouse model that forms the centerpiece of our continuation.”

Parker says the interesting thing about this model is that the researchers can follow the progression of disease in the mice from normal to swollen corneas and identify early markers of disease that provide insights into the pathological mechanisms at work. 

“Our preliminary data have highlighted that one of the genes whose expression is unexpectedly downregulated prior to onset of disease, encodes a long non-coding RNA that coordinates the stress response to ultraviolet (UV) light,” Parker notes.

“This suggests that the SLC4A11 mutant somehow predisposes the cornea to UV-sensitivity and that UV-protective measures may be effective at slowing vision loss in individual with such mutations.”

Having established that the mutant-mice model FECD, the researchers now need to establish whether, as expected, the corneas of these mice are more susceptible to UV-damage.

“We are also interested to work out why some mutations in SLC4A11 cause the congenital swelling while others cause slow onset,” Parker says. “Are they extremes of the same disease spectrum or are there unexpectedly, as our results might suggest, entirely different mechanisms at work?”

The grant application scored in the 2^nd percentile, according to the NIH, with its reviewers writing “overall, the panel considered this to be an outstanding application from a productive investigator, that’s likely to have a strong impact on our understanding of FECD.”

Parker notes the study of a mouse model of late-onset corneal dystrophy allows for the development and testing of novel therapies and interventions — such as antioxidant eye drops — to slow or prevent disease progression.

Parker also has an appointment with the Department of Ophthalmology.

Co-investigators on the study from the Jacobs School of Medicine and Biomedical Sciences are:

• Michael E. Duffey, PhD, professor of physiology and biophysics
• Michael H. Farkas, PhD, assistant professor of ophthalmology
• Sangita P. Patel, MD, PhD, clinical assistant professor of ophthalmology

Derek L. Beahm, PhD, assistant professor of biology at Buffalo State University, is also a co-investigator.