DETROIT- Preventing the progression of the most common and serious eye-related complication of diabetes is the aim of three separate studies by researchers in Wayne State University's School of Medicine. The Juvenile Diabetes Research Foundation awarded nearly $900,000 to WSU faculty for research focusing on different aspects of retinal damage in the early stages of diabetic retinopathy, the leading cause of blindness in young adults.

Renu Kowluru

Bruce Berkowitz

Pukhrambam Singh

Diabetic retinopathy is characterized clinically by the appearance of small, dot-like hemorrhages in the retina and the development of new blood vessels. These new vessels are delicate and hemorrhage easily, causing blood to leak into other parts of the eye. In its most severe stages, scar tissue around the blood vessels can cause the retina to detach from the back of the eye, resulting in blindness.

Ninety-five percent of people with diabetes develop some form of diabetic retinopathy, typically after about 20 years of living with the disease. Of those, 20 to 30 percent reach the advanced form that can lead to blindness.

Renu Kowluru, Ph.D., professor of ophthalmology and anatomy/cell biology and resident of West Bloomfield, Mich., received $453,750 to investigate the role of enzymes called metalloproteinases in the collapse of retinal capillaries in diabetes patients. Kowluru's hypothesis proposes that metalloproteinases are activated due to an increase in oxidative stress, which occurs as a result of high glucose levels early in the progression of diabetic retinopathy. Activated metalloproteinases accelerate cell death in the capillaries of the retina, which then causes the blood vessels to collapse and ultimately results in retinal detachment and blindness.

Kowluru's research focuses on how changes in the activation of the metalloproteinase MMP-2 results in the loss of capillary cells. Understanding the signaling mechanisms of MMP-2 that modify the course of retinopathy could reveal important molecular targets and help in the design of specific therapeutics.

"This is one of many metabolic pathways that contribute to the development and progression of diabetic retinopathy," Kowluru said. "If we can block that pathway, we may stop the condition from progressing any further. This would be a tremendous step forward because it may stop irreversible damage."

Bruce Berkowitz, Ph.D., professor of anatomy/cell biology and ophthalmology and resident of West Bloomfield, Mich., received $297,516 to identify the window of time during the pre-clinical phase of diabetic retinopathy in which drug intervention would be the most successful. Berkowitz will use a manganese-enhanced MRI method to measure retinal ion activity - an indicator of the retina's overall health. In a previous study, irregular ion activity preceded clinical signs of diabetic retinopathy. Although it is not yet clear how ion activity and blood vessel damage are related, the study showed that correcting the impairment in ion activity in the retina prior to the onset of clinical symptoms prevented the development of diabetic retinopathy in animal models.

"With diabetic retinopathy, there is functional damage to the retina that occurs well in advance of clinical, detectable damage," Berkowitz said. "It's during this stage, which we refer to as ‘emerging diabetic retinopathy,' in which we have the best chance to intervene. The goal of this study is to determine when in this stage it is best to intervene, and what type of intervention would be most useful."

Pukhrambam Singh, Ph.D., assistant professor of anatomy/cell biology and ophthalmology and resident of West Bloomfield, Mich., received $109,854 to investigate the role of the protein TXNIP in early endothelial dysfunction in diabetic retinopathy. Endothelial cells line the inner walls of blood vessels, forming tight junctions to prevent leakage. In diabetes patients, however, endothelial cells fail to function properly, causing blood vessels in the capillaries to leak. Singh believes endothelial dysfunction is in part caused by high glucose levels activating TXNIP.

"TXNIP could be one of the triggering proteins for diabetic retinopathy," Singh said. "By silencing this protein, we could prevent blood leakage and subsequent molecular events, preventing the progression of the disease."

Wayne State University is one of the nation's pre-eminent public research universities in an urban setting, ranking in the top 50 in R & D expenditures of all public universities by the National Science Foundation. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world.