An innovative take on hindering the development and progression of diabetic retinopathy will continue through 2023 at the Wayne State University School of Medicine's Kresge Eye Institute thanks to a renewed five-year grant for $1.9 million from the National Eye Institute of the National Institutes of Health.

Diabetic retinopathy is the most frequent cause of blindness among young adults, but the underlying molecular and cellular mechanisms remain vague, said Professor of Ophthalmology and of Anatomy and Cell Biology Renu Kowluru, Ph.D.

She and husband Anjan Kowluru, Ph.D., a professor of Pharmaceutical Sciences and Veterans Affairs Senior Research Career Scientist, are the principal investigators on the project, which was initially awarded a four-year R01 grant in 2012.

"Data from our originally-funded project have suggested that activation of NADPH oxidase (Nox2) and subsequent generation of reactive oxygen species (oxidative stress) represent a key signaling step to promote mitochondrial damage, leading to retinal endothelial cell death and the development of diabetic retinopathy. We have also identified novel roles for Rac1, a small G protein, in the activation of Nox2," Dr. Renu Kowluru said.

The renewal application will test the central hypothesis that covalent modifications of Rac1 regulate its functional and transcriptional activation in diabetes.

"We will test the hypothesis in a methodical fashion in isolated retinal endothelial cells in culture, and in retinal microvessels from (pre-, type 1 and type 2) diabetic rodent models and from human donors with established diabetic retinopathy. Our first two aims are to gain a deeper understanding of the mechanisms underlying Rac1 activation. The third aim will focus on testing novel small molecule inhibitors of these pathways in animal models of type 1 and type 2 diabetes," she added. "It is our hope that data accrued from these investigations, involving state-of-the-art methodologies, could have a significant impact in developing new therapies to inhibit the development and progression of diabetic retinopathy."

The plan represents continued multi-disciplinary collaborative efforts between two well-established laboratories to precisely understand the mechanisms underlying Rac1-Nox2 activation in the pathogenesis of diabetic retinopathy.

"This plan also has a significant translational impact, as we expect to identify novel therapies to treat and prevent this sight-threatening complication of diabetes," she said.

During the previous funding period, Drs. Kowluru and team accrued and published 17 papers directly related to the central role for Rac1-Nox2 signaling as the mediator of increased oxidative stress- mitochondrial damage.

The review panel expressed a high degree of enthusiasm for the proposed innovative studies, and viewed the renewal application as outstanding, Dr. Kowluru added.

This research is funded by the National Eye Institute of the National Institutes of Health (EY022230).