Wednesday, March 22, 2023
3/22/2023
PROJECT SUMMARY Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the United States. AMD is characterized by the death of photoreceptors and their supporting cells, the retinal pigment epithelium (RPE). The Dunaief lab has previously demonstrated that iron accumulates in the photoreceptors and RPE of AMD patients compared to age-matched controls. Subsequent in vitro and in vivo work demonstrated that iron accumulation is sufficient for retinal degeneration. Furthermore, iron chelation therapy is protective against retinal degeneration secondary to a diverse array of toxins and genetic mutations associated with AMD. However, the mechanism of iron accumulation in AMD is not known. In this proposal, we utilize magnetic cell sorting technology paired with molecular biology techniques in human and mouse retinal tissue to test our hypothesis: IL-1ß triggers retinal iron accumulation in photoreceptors and RPE, exacerbating AMD. In Aim 1, we will isolate cell fractions from AMD and normal retinas to determine which cell-types produce IL- 1ß and which cell-types express the receptor proteins necessary for IL-1ß signal transduction. We will also measure mRNA and protein levels of iron transporters in each cell fraction to identify which transporters contribute to retinal iron overload in the photoreceptors and RPE. In Aim 2, we will use cell sorting to isolate retinal cell fractions from a mouse model of chronic neuroinflammation. We hypothesize that IL-1ß and IL-1ß receptor, IL-1R1, are necessary for iron accumulation and iron transcriptome changes secondary to a chronic inflammatory stimulus. We also hypothesize that chronic administration of IL-1ß, delivered to retina using an adeno-associated virus, will be sufficient for changes in the retinal iron transcriptome and iron accumulation. Together these data will determine (1) if IL-1ß signaling may serve as a trigger for retinal iron accumulation in AMD and (2) whether IL-1ß inhibition can be used to prevent iron accumulation in photoreceptors and RPE. This grant will provide indispensable support towards my training as an aspiring scientist-ophthalmologist so that I can achieve my ultimate goal of fusing clinical and basic science ophthalmology to create better therapies for retinal disease.
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