Saving Sight by Reprogramming the Metabolism of Photoreceptors

Cagri Besirli, M.D., Ph.D., with Mercy Pawar, a research lab technician in the Besirli Lab.

Cagri Besirli, M.D., Ph.D., with Mercy Pawar, a research lab technician in the Besirli Lab.

A defining characteristic of retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa, is damage to photoreceptor (PR) cells in the retina. PR cells sense light and trigger signals to the brain to receive an image. As PR cells deteriorate, images grow blurry or distorted, and eventually, disappear entirely.

Currently, no treatments exist to reverse or repair PR damage.

A team led by Cagri G. Besirli, M.D., Ph.D., Skillman Career Development Professor of Pediatric Ophthalmology and an assistant professor of ophthalmology and visual sciences, believes that boosting the metabolism of PR cells may improve their survival.

A critical component of PR cell metabolism is aerobic glycolysis, a specialized process of efficiently using energy stored in glucose molecules in cells with high metabolic needs. Dr. Besirli hypothesizes that by modifying two genes that drive aerobic glycolysis, PR cells can be reprogrammed to survive longer. The first, HK2, is believed to act as an intracellular control switch, linking energy needs and metabolism to cell dysfunction and death. The second, PKM2, serves as a gatekeeper of energy activity within the cell, shifting glucose to generate building blocks for the cell or to produce energy.

Using several approaches, Dr. Besirli plans to manipulate HK and PKM function, effectively reprogramming the metabolism of PR cells. This would improve their ability to make energy efficiently, and slow PR cell death during energy crises.

Studies made possible by this NEI (NIH) R0-1 grant will lay the foundation for continued exploration of connections between metabolism and PR survival during retinal stress, and may lead to new treatment targets for retinal diseases.