Impact of Sex on Mitochondrial and Epigenetic Mechanisms in Age-Related Macular Degeneration - PROJECT SUMMARY Age-related macular degeneration (AMD), a chronic neurodegenerative condition, is the leading cause of irreversible vision loss, and more prevalent in women over 60 years. AMD cannot be prevented or cured, and is heterogeneous in its clinical presentation. The intermediate form of AMD may be a clinical biomarker indicating an increased risk of progression to either of the two advanced forms: neovascular AMD (also referred to as wet AMD), which correlates with rapid vision loss; and geographic atrophy (GA also referred to as dry AMD), in which it can take longer for vision loss to occur. Most patients are asymptomatic in the intermediate stages of AMD and do not seek clinical care. AMD involves the progressive degradation of the macula, which is responsible for sharp visual acuity. This impairs reading, facial recognition, and driving abilities, correlating with increased social isolation, clinical depression, and anxiety (all more common in women). Treatments are limited in efficacy for both the wet and dry forms and the outcome is vision loss. While progress has been made in terms of the genetic loci associated with AMD risk, therapies to prevent or halt disease progression have not yet been approved by the FDA. This is due in part to the lack of appropriate animal models that fully recapitulate the AMD phenotype, as affected tissue (eg., the maculae of the retina pigment epithelium (RPE)) are unique to the human eye. Given that the prevalence of AMD will increase to almost 300 million people globally (with nearly 200 million comprised of women) by 2040, there is clearly an unmet clinical need that must be urgently addressed. Increasing evidence has demonstrated that dysfunction in the epigenetic landscape of the nuclear genome and the mitochondrial genome (mtDNA) play a significant role in chronic progressive neurodegenerative diseases of aging, including Alzheimer’s disease and AMD. Moreover, it may be the epigenetic interplay between the nuclear genome and the mitochondrial genome that exacerbates the development and progression of disease. Based on our novel preliminary data derived from well-characterized human donor eyes with intermediate and late stages of AMD, we hypothesize that the interplay between the mitochondrial and nuclear genome architectures is a significant driver of the sex-specific manifestations of macular RPE and choroid dysfunction across the clinical spectrum of AMD. Based on this preliminary data, we propose to leverage 48 well-characterized sex and age-matched donor eyes with and without AMD (intermediate, GA, wet and normal) from the macula RPE/choroid; from our existing donor eye repository to 1) Generate a comprehensive of mtDNA variation 2) Elucidate DNA methylation and chromatin accessibility changes in the nuclear and 3) Integrate the new datasets along with our existing single- cell RNASeq data to functionally characterize the interplay between the nuclear and mitochondrial genomes in AMD. Our study will provide novel sex-specific biological mechanisms that can drive sex specific therapeutic targeting for this blinding condition.
