Exploring How NRF2 Protein Reduces RPE Cell Damage by Cigarette Smoke

The goal of this project is to explore how acetylation of the NRF2 protein can restore impaired NRF2 signaling in the retinal pigment epithelium (RPE) and improve RPE function during chronic smoke stress, a causative factor for AMD progression.

In age-related macular degeneration (AMD), retinal pigment epithelial (RPE) cells are damaged by oxidative stress. NRF2 is a protein that protects against oxidative stress; however, NRF2 signaling declines in AMD. Dr. Singh and his team propose to find a cause for NRF2 signaling decline, called acetylation, a process that modifies proteins to change how genes are produced. Researchers will treat RPE cells with smoke and verify if the acetylating NRF2 will prevent its decline. If successful, they will have a favorable strategy for treating AMD.

The research proposal is innovative with its focus on NRF2 protein acetylation modulation of the antioxidant protection in the RPE in response to cigarette smoke stress. Specifically, the novel hypothesis that a pathological decrease in the acetyltransferase or an increase in the deacetylase disrupts NRF2 acetylation to impair its protective signaling and link its role to AMD pathobiology. If correct, this study will uncover an unrecognized mechanism of NRF2 regulation in AMD, and open new avenues for therapeutic intervention.

By elucidating the mechanisms of NRF2 acetylation and its role in protecting RPE from cigarette smoke-induced oxidative stress, new therapeutic strategies for AMD could be developed. These findings could pave the way for novel antioxidant treatments targeting NRF2 acetylation, potentially delaying or preventing AMD progression, particularly in the elderly and also those who smoke. Additionally, this research could provide valuable insights into the broader impacts of oxidative stress on cellular health and aging, fostering further advancements in age-related disease prevention and treatment.