Identification of the specific risk allele responsible for oxidative stress in ARMS2/HTRA1-related AMD

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PROJECT SUMMARY Until now, CRISPR has not been readily applied to isolate linked genome-wide association studies (GWAS) alleles as Cas9 tends to re-cut the donor template. Our project will be the first to establish that CRISPR-edited cells can be used to isolate closely linked alleles in a GWAS-associated disease. Furthermore, research on age-related conditions uses traditional cultured cells as the metabolic backdrop for studies. Given that these rapidly proliferating cells more closely resemble embryonic cells than aged adult cells, they likely do not provide the appropriate environment to study the molecular biology of aging. Here, we propose to use cells that have been pharmacologically aged, enabling our model to better recapitulate the conditions present in the older adult eye, and ultimately identify appropriate areas of intervention. By using this innovative approach, we will develop a patient-specific disease model to test not only the particular mutations addressed in this application, but also other mutations and, potentially, other age-related retinal diseases down the road.