We have documented the loss of choriocapillaris (CC) in all stages of age-related macular degeneration (AMD) during the past 4 years. In early and intermediate AMD, the previously undocumented loss of CC was often accompanied by hyperplastic vascular structures or buds that we presume are the earliest form of choroidal neovascularization (CNV). In geographic atrophy (GA) the significant CC loss appeared to occur after the retinal pigment epithelium (RPE) have atrophied. In neovascular AMD, the loss is adjacent to CNV where there is a monolayer of RPE present, so CC loss precedes RPE loss. We now want to investigate the cause of CC and RPE loss. Recent work suggests that inflammation is involved in AMD. We find that choroid is a proinflammatory milieu, having elevated C-Reactive Protein (CRP), complement components (C3a, C5a, C5b-9), and advanced glycosylation end products. We recently investigated the inflammatory cells of choroid: macrophages and mast cells (MCs). There were increased numbers of activated macrophages (IBA1+/HLA-DR+) in AMD choroid. There were significantly more MCs and more degranulating MCs in all AMD choroids. Degranulation was often associated with pathological changes in the CC. These results suggest the following hypothesis: choroidal MC degranulation results in thinning of choroid, death of RPE and CC, and activation of choroidal macrophages, events that occur in AMD.
In Aim 1, we will use a rat model of choroidal MC degranulation to determine the effects of MC degranulation on a normal choroid.
Aim 2 focuses the effect of MC degranulation after different stimuli, which are known to be present and elevated in AMD choroid, on RPE and choroidal endothelial cell (CC EC) viability and formation of a monolayer in vitro. MC quiescence has been the focus of pharmaceutical companies for years so we hypothesize that MC degranulation is a druggable target and quiescing and stabilizing MCs can curtail progression of the AMD phenotype in our rat model. To address this hypothesis, we will focus in Aim 3 on FDA approved topical drugs (Chromolysin, Ketofilin fumarate) and determine if topical or oral administration prevent choroidal MC degranulation in our rat model and prevent induction of AMD like changes in choroid. Finally, in Aim 4, we will characterize the choroidal MCs in AMD versus aged controls and assess the choroidal milieu in clinically documented human AMD versus aged control subjects without AMD to elucidate new targets for therapy to prevent degranulation. The proposed studies have the potential to elaborate the role of choroidal MCs in AMD and potentially demonstrate that generic FDA-approved drugs could be repurposed to control MC degranulation and allay progression of AMD.
Geographic atrophy (GA), a form of dry age-related macular degeneration, is characterized by loss of retinal pigment epithelial cells and choroidal endothelial cells as well as thinning of choroid. We hypothesize, based on our recent study published Brit. J. Ophthalmol., that mast cells in choroid degranulate in GA and all AMD stages, causing this cell loss and thinning. We propose to evaluate two FDA-approved generic drugs that can stabilize and quiesce mast cells in our rat model of mast cell degranulation to determine if they can prevent mast cell-induced cell loss and choroidal thinning.
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