Oxidative stress-driven inflammation is a key driver of many age-related diseases, including those that cause blindness. Bhavana Chhunchha, PhD, assistant professor in the UNMC Department of Ophthalmology and Visual Sciences, has found that deterioration of the antioxidant pathway Nrf2 is a major contributor to oxidative stress accumulation in aging eye lenses and lens cells. This, in turn, promotes inflammation-driven cell death and the onset of age-related cataract formation.
The deterioration of this antioxidant pathway is a previously unknown link in the oxidative stress-driven inflammatory process, Dr. Chhunchha said — a discovery that points toward potential interventions.
Dr. Chhunchha has received a five-year, $1.92 million grant from the National Institutes of Health (NIH) National Eye Institute to study the causes of inflammatory signaling, including the genes and proteins responsible. She aims to identify clues that could support a gene-based therapy using small molecules and will test both pharmacological and genetic approaches to block the oxidative stress-driven inflammatory response.
Dr. Chhunchha hopes her work in eye lenses and lens cells may prove applicable across a range of age-related pathologies.
“Aging and oxidative stress share common molecular denominators and are the prime risk factors for many age-related blinding diseases, including cataract,” Dr. Chhunchha said.
She was intrigued that age-related pathologies share a series of common pathogenic factors — raising the question of whether treating or delaying one age-related pathology might benefit others. By studying this process in the eye lens, she hopes to reveal aging pathobiology and investigate the molecular mechanisms behind Nrf2 deterioration, and to apply the findings across age-related and oxidative stress-related pathologies.
Dr. Chhunchha and her team have already shown in preliminary data that deteriorated Nrf2-dependent antioxidant survival signaling in aging eye lenses can be revived — and oxidative stress-induced inflammation and lens opacity halted — with the FDA-approved drug metformin. Her UNMC lab has demonstrated this in in vitro, in vivo, and ex vivo studies.
The team has further found that aging lenses and lens cells under oxidative stress, with reduced antioxidant signaling, show a dramatic increase in expression of the transcription factor Klf9. This suppresses Klf9-dependent antioxidant genes and activates the inflammatory signaling mediator NF-κB.
“This suggests that by blocking aberrant activation of Klf9 and NF-ĸB and restoring the dysregulated antioxidant response during aging through small-molecule intervention, age-related diseases like cataract could be halted,” Dr. Chhunchha said.
“The study of oxidative stress pathways by Dr. Chhunchha and her colleagues at UNMC is important in understanding a host of age-related blinding disorders, such as cataract, that impact millions of people around the world,” said Ronald Krueger, MD, chair of the UNMC Department of Ophthalmology and Visual Sciences and director of the Truhlsen Eye Institute.
“This research will help researchers around the world understand how inflammation-driven damage to critical lens cells could potentially be halted,” said Dhirendra Singh, PhD, professor of ophthalmology and visual sciences at UNMC.