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.