We have recently completed a whole-genome scan of a large cohort of case-controls for finding new AMD-associated variants. Replication studies suggest that a new region on chromosome 22 is associated with susceptibility to AMD. Based on the GWAS study, we performed follow-up genotyping to narrow down a susceptibility region. Furthermore, we established a protocol for gene transfer into the developing mouse retinal pigment epithelium (RPE) using in vivo electroporation. Utilizing this technique, we have studied the roles of genes implicated in AMD identified through GWAS. Genes involved in cholesterol metabolism and transport are being evaluated by RNAi-mediated knockdown studies. Information about the functional contribution of these genes in RPE cell physiology and maintenance could lead to further elucidation of the etiology of AMD. We recently identified a key AMD-susceptibility variant in ARMS2 gene that encodes a mitochondrial protein based on in vitro cell culture studies. We have generated a number of ARMS2 antibodies to perform in vivo localization of ARMS2 protein in human and monkey retina. We are also examining how a specific insertion-deletion polymorphism can lead to AMD susceptibility. Finally, we are determining cellular/functional changes associated with aging of the retina in order to understand their contribution to the onset of retinal degeneration. We have combined microarray analysis of flow-sorted rod photoreceptors from young and aging mice, validated with qPCR and IHC, with electroretinograms and a novel method (Seahorse XF24 Analyzer) to measure mitochondrial function in enzymatically-dissociated retina cells.
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