Renu A. Kowluru, Ph.D., professor of ophthalmology, anatomy/cell biology and endocrinology at Wayne State University and the Kresge Eye Institute, recently received a one-year, $110,000 Innovative Grant from the Juvenile Diabetes Research Foundation to help gain new insight into the development of diabetic retinopathy and identify targets for future therapeutic interventions.
Her hypothesis is that NF-E2-related factor 2 (Nrf2), a protein that regulates antioxidant response, fails to reach to the nucleus of cells in the retina to neutralize free radicals, which are volatile. As a result, Kowluru said, KEAP1 - the protein that serves as an anchor for Nrf2 and represses its activation - increases, damaging the mitochondria, the cells' power source. That damage, she believes, in turn accelerates the death of cells in tiny blood vessels (capillaries), ultimately resulting in the development of retinopathy.
Diabetes is a leading cause of acquired blindness in young adults. Almost 50 percent of diabetes patients have some form of retinopathy - not necessarily blindness - after nine years, and that figure increases to 95 percent after 20 years of the disease.
"Basically it doesn't leave any diabetic patient," Kowluru said.
Titled "Role of Nrf2-KEAP1 in Diabetic Retinopathy," her project will look at the oxidative stress, an imbalance between the production and utilization of free radicals, in an effort to determine how a disease state - diabetes in this case - causes that imbalance.
"We have shown that in diabetes, mitochondria are damaged, and when they are damaged they initiate cell death," Kowluru said. "We want to see what the role of Nrf2 is in initiating this signal."
Beginning in October, her team will genetically regulate Nrf2 to examine the temporal relationship between the failure of the protein to reach cells' nuclei and the signal sent by damaged mitochondria that triggers cell death. She hopes to determine if the former event precedes the latter, or if they occur at the same time.
Additionally, Kowluru will examine the point on the gene where Nrf2 and KEAP1 interact to determine whether diabetes induces epigenetic changes in Nrf2, impairing its binding with KEAP1.
Because epigenetic changes, which are functionally relevant modifications to the genome that do not involve a change in the DNA sequence, can be passed along to future generations, prevention becomes an even more important goal, she said. Drugs now in the clinical trial stage for other chronic diseases (e.g., cancer) may be able to prevent epigenetic changes in the retina.
"Once we understand the problem, we can administer supplements and prevent the downstream pathway for retinopathy," Kowluru said.
Provided by Wayne State University
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