Sunday, November 24, 2024
11/24/2024
Project Summary Age-related macular degeneration (AMD) is the leading cause of irreversible visual dysfunction in older individuals although its underlying causes have not been definitively elucidated. Human cytomegalovirus (HCMV) infection could be a risk factor for progression of AMD since there is a significantly higher association of elevated anti-HCMV IgG titers with neovascular AMD compared to either “dry” AMD or healthy controls while HCMV DNA has been identified in choroid/RPE samples from human cadavers. Our published and preliminary studies have shown that: (1) systemic neonatal murine cytomegalovirus (MCMV) infection of both BALB/c and 129S1 mice spreads to the eye with subsequent establishment of latency in the choroid/RPE; (2) retinal and choroidal pathologies, including deposits at both basal and apical aspects of the RPE, CNV-like lesions, as well as degeneration of the choriocapillaris, RPE and photoreceptors occurs in aged, infected BALB/c mice; (3) CNV lesions develop in eyes of aged 129S1 mice following systemic neonatal MCMV infection; (4) hyperreflective lesions are present in the majority of infected, tamoxifen-inducible, RPE- specific, SOD2 depleted 129S1 mice; and (5) RPE-specific, SOD2 depletion enhances spread of latent MCMV to the RPE. Based on these findings we hypothesize that oxidative stress following light damage, activates expression of ocular virus genes, which in turn, promotes production of inflammatory/angiogenic factors in MCMV latently infected mice, thereby facilitating the development of AMD-like pathology, including CNV. Aim 1 will test the hypothesis that light damage and virus latency synergize to enhance the development of AMD- like pathology. We will compare the development of AMD-like pathology in neonatally infected or uninfected, aged BALB/c mice maintained under either low or regular-illumination. Aim 2 will test the hypothesis that oxidative stress in the RPE and MCMV latency synergize to enhance development of AMD-like pathology. We will induce mitochondrial oxidative stress by depletion of SOD2 in RPE cells and determine the effect of oxidative stress on expression of MCMV latency-related genes, production of inflammatory angiogenic factors and the development of AMD-like pathology. Aim 3 will test the hypothesis that release of angiogenic factors by latently infected RPE cells is the mechanism by which latent ocular MCMV induces CNV. We will define the location and identity of latently infected cells and quantify expression of MCMV latency-related and inflammation/angiogenesis-associated genes in aged, latently infected eyes, both with and without CNV. These studies will: 1) establish an in vivo mouse model of systemic neonatal MCMV infection and oxidative stress, featuring the development of AMD-like pathologies; 2) increase our understanding of the synergy between light damage, oxidative stress and virus latency in the development of AMD and 3) identify the mechanism by which latent MCMV infection of the choroid, RPE and macrophages/microglia induce CNV.
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