The Role of Aging, Diet, and Inflammation in RPE Degenerative Processes

We want to understand the role of subretinal and choroidal macrophages in the degeneration of the retinal pigmented epithelium (RPE) with aging and unhealthy diet, important risk factors for age-related macular degeneration (AMD).

AMD is a blinding disease in which the cells that process visual information, photoreceptors, degenerate and die. This neurodegeneration is partly due to failure of the retinal pigmented epithelium (RPE), the tissue that lies beneath the retina, to support normal tissue structure and visual function. Aging is the main risk factor for AMD, but diet and inflammation also increase AMD risk. Our proposed research aims to study how aging and diet interact with immune cells, microglia and macrophages, to affect the RPE genetic programs and function for discovery of candidate targets to treat AMD.

No aging studies have addressed the role of retina microglia (MG) and choroidal macrophages (Mo) in retinal pigmented epithelium (RPE) responses to a Western diet (WD) in both sexes. Using mouse models to tag ribosomes in a cell type-specific manner, sequencing, and tissue function correlates our studies will be the first to: 1) define spatiotemporal distribution and transcriptomes of retina MG and Mo from the same mice, with aging and WD, 2) analyze the RPE transcriptome with aging and WD, 3) study the effect of sustained vs short term MG depletion on RPE responses/dysfunction with age and WD.

Our study will provide insights into the mechanistic cross-talk between retinal pigmented epithelium (RPE) and local macrophages, addressing technical and conceptual gaps in the field that prevent the understanding of mechanisms of age-related RPE degeneration and AMD. We foresee the provision of deliverables for the development of therapeutic interventions to promote healthy retina aging. A primary deliverable outcome of these studies will be RPE and macrophage candidate targets for potential manipulation to prevent/reverse maladaptive RPE/retina aging and by extension, AMD risk.