Immune Cell Specific DNA Modifications and Gene Expression in Age-Related Macular Degeneration

Aging is the major risk factor for age-related macular degeneration (AMD) but how aging, along with sex, lead to the development of the disease is not understood. DNA alterations that do not change genetic composition, known as epigenetic modifications, are able to influence gene expression. Epigenetic modifications, principally methylation (mC)and hydroxymethylation (hmC) of the DNA have been linked to the development/progression of AMD, but how these alterations change with aging and sex in the different cell types of the retina, including microglia and Müller glia, is not known. Using novel mouse models that allow the isolation of DNA and RNA from specific cell types, Specific Aim 1 and Specific Aim 2 will evaluate mC and hmC and how such modification correlate with gene expression and retina function/acuity specifically in microglia and Müller cells, respectively, taking into account age and sex as parameters.

Our project seeks to understand how the retinal epigenome (the organization and function of the genome) changes with aging and contributes to age-related macular degeneration (AMD). The retina is made up of a variety of cells in addition to the rods, cones, and neurons that allow you to see. We are particularly interested in the glial cells, which control inflammation in the retina. Microglia and Muller glia are two types of glial cells for which we have engineered mice that allow us to specifically analyze the epigenome and transcriptome from these cells. Using these special mice we will examine age related changes in DNA modifications, a type of functional mark on the genome, and gene expression in both males and females. Given sex effects in age-related inflammation understanding commonalities and differences between males and females is a central goal of our research. These studies will bring both these unique mouse models and new techniques to measure the epigenome to AMD research for the first time. This type of cell-type specific data across the lifespan has not been generated for the retina and we hope will provide new insights into how aging contributes to AMD risk. The results of this study will both identify candidate targets for cell- and sex-specific epigenome editing to prevent or reverse maladaptive retina aging and serve as a resource to the AMD research community.