Research funded by a new grant awarded to Professor Renu Kowluru, Ph.D., from the National Institutes of Health could help prevent the development and progression of a sight-threatening complication of diabetes. 

The National Eye Institute funded the project, “Diabetic Retinopathy, Mitochondria Damage and Long Non-coding RNAs,” of which Dr. Kowluru, director of Translational Research in the Department of Ophthalmology, Visual and Anatomical Sciences, is principal investigator.

The five-year, $1.8 million award is her fourth active R01 this year, an honor shared by less than 5% of the NIH-funded principal investigators.

Diabetic retinopathy, the most common cause of acquired blindness in young adults, results from damage to the small blood vessels in the retina. All people with diabetes are at risk of developing retinopathy, and the risk increases the longer a person has diabetes.

“Reviewers commented that it was on an ‘important subject,’ highly innovative, rigorously and logically designed, and significant application that is expected to have a high and sustained impact on the field,” Dr. Kowluru said.

In the first year of the five-year grant, the Kowluru laboratory’s team of scientists will work to understand the role of mitochondrial DNA-encoded long noncoding RNA in mitochondrial stability.

“This could help identify novel therapeutic targets to break the vicious cycle of free radicals, which self-propagate in diabetes,” she said.

They hope to identify regulatory mechanisms involved in the pathogenesis of diabetic retinopathy by the end of the grant period, specifically at the level of mitochondrial DNA-encoded LncRNA in mitochondrial homeostasis. Successful completion of the studies will provide strong background for mitochondrial DNA encoded long noncoding RNA Cytochrome B as a potential therapeutic target to prevent the development and progression of the disease.

The Kowluru lab is focused on mitochondrial homeostasis in diabetic retinopathy.

“We are the first one to show the role of epigenetics in impaired mitochondrial stability. We are now working on how diabetes affects mitochondrial dynamic, why damaged mitochondria are not removed and how epigenetic modifications affect these processes. This project will add a novel direction by focusing on the long noncoding RNAs, specifically, long noncoding RNA encoded by mitochondrial DNA,” she said.

In the pathogenesis of diabetic retinopathy, retinal mitochondria are damaged and the electron transport chain system is compromised, fueling in a vicious cycle of free radicals. Diabetes also alters expression of many long noncoding RNAs, and the RNAs with more than 200 nucleotides lack an open reading frame for translation. Mitochondrial DNA encodes three LncRNAs, but their role in regulating mitochondrial homeostasis in diabetic retinopathy is not clear.

LncRNA Cytochrome B is important in the functioning of complex III in maintaining mitochondrial homeostasis in diabetic retinopathy. “These studies carry a significant translational impact as they are expected to identify LncRNA Cytochrome B as a novel therapeutic targets to prevent the development and progression of diabetic retinopathy, offering patients additional means to prevent or halt this sight-threatening complication of diabetes,” Dr, Kowluru said.

The number for this National Institutes of Health award is R01EY033516.