Modeling the effect of outdoor air pollution on the health and function of the retina

Pollution levels in the USA are rising due to climate change, wildfires and increased vehicle traffic. Recent epidemiological studies indicate that air pollution is a contributing factor to AMD, glaucoma and other ocular diseases. Health risks from air pollution are mostly attributed to fine particulate matter

smaller than 2.5 microns (PM2.5) that can induce oxidative stress, DNA damage and activate inflammatory pathways throughout the body. Indeed, PM2.5 levels are correlated with increased incidence of AMD, glaucoma, elevated IOP and changes to the RPE, outer segment layer, and retinal arterioles. However, the molecular changes induced by acute and chronic outdoor air pollution in the

retina and the role of intrinsic protective tissue responses in reducing damaging effects of pollution are not understood. Furthermore, the molecular and cellular effects of air pollution in association with age or AMD-like risk factors has not been examined. Therefore, much remains to be defined about the

underlying mechanisms of pollution-induced retinal damage and there is a clear need to generate and characterize reproducible animal models of PM2.5-induced retinal disease. This proposal addresses an understudied yet highly significant area of environmental health and ophthalmic research. A newly designed animal housing unit overcomes prior technical barriers by allowing whole-body exposure of

defined PM2.5 pollutants at specific concentrations. Our overarching hypothesis is that aerosolized PM2.5 induces specific oxidative stress and inflammation pathways and alters intrinsic tissue protective responses, leading to retinal pathology in wildtype mice, and that damage is exacerbated in retinas

susceptible to pollution from aging and underlying AMD-like pathology. Aim 1 will test the hypothesis that PM2.5 pollution exposure causes sustained inflammatory changes in the retina and alters intrinsic cell stress responses. We will measure aerosolized PM2.5-induced molecular and cellular changes in

normal, aged and AMD-like mouse retinas over time, using flow cytometry, cytokine assays and scRNAseq. Aim 2 will test the hypothesis that PM2.5 exposure accelerates the rate and extent of retinal pathology in aged and AMD-susceptible mice. Therefore, this study will have an important impact on the field by developing new mouse models used to characterize pollution effects, define the natural

history of pollution-induced retinal pathology, characterize underlying mechanisms of pollution-induced retinal damage and intrinsic tissue responses, and will identify targets for future study and therapeutic intervention.