Development of In Vitro Models to Study the Effects of Wound Repair and Aging in Retinal Pigmented Epithelium
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Development of In Vitro Models to Study the Effects of Wound Repair and Aging in Retinal Pigmented Epithelium

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Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in people over the age of 50 in the western world. Nearly 2 million people in the U.S. were affected in 2010, and as life expectancy increases, the number of people with AMD will also increase. By the year 2030, it is estimated that over 3 million people in the U.S. alone will be diagnosed with AMD. Although early signs of AMD can be identified easily by a fundus photograph taken by an ophthalmologist, little can be done to cure the disease. Once AMD progresses to advanced stages, irreversible central vision loss can occur, eventually resulting in blindness. In addition to the effect on quality of life, the economic burden of AMD is estimated to be over $340 billion globally. Early AMD can progress into two advanced stages termed wet or dry AMD based on the presence of choroidal neovascularization. Although wet and dry AMD are clinically distinct, they both are triggered by the degeneration of the retinal pigmented epithelium in the macula, the area responsible for central vision. Retinal pigmented epithelial (RPE) cells are a cuboidal, polarized, and highly pigmented monolayer located between the visual photoreceptors and the vascular choroid. They are an essential cell type in the retina as they provide nutrients, support the visual cycle, and remove waste and fluids from the retina, among other functions. Degeneration and the failure of this single layer of cells to repair can have devastating impacts on retinal function and can ultimately result in the death of the overlaying photoreceptors. The pathogenesis driving AMD is not entirely clear, but numerous risk factors have been identified including genetic variants and environmental stressors, but the number one risk factor is age. The lack of treatments for early and advanced stages of AMD can in part be explained by the lack of appropriate cell culture and animal models which recapitulate the progression of the disease. My Ph.D. research focuses on the development of novel in vitro wounding platforms to analyze the innate ability of human RPE to repair. In chapter II, we discuss the development of a platform to induce a state of chronic wounding in RPE monolayers. Chronic wounding resulted in several AMD phenotypes including enlarged cell size and multinucleation, along with an increased inflammatory response. In chapter III, we examine a large macula-sized wounding platform. In this system, RPE cells failed to adequately repair, resulting in loss of cuboidal morphology, loss of pigmentation, and regions of RPE atrophy. Finally, in chapter IV, we use a transcriptomic approach to analyze age-related changes in RPE and how it may affect the ability of RPE to repair wounds in the monolayer. Taken together, the work presented here further our knowledge of RPE wound repair and may also allow for the identification of therapeutics which can improve the ability of RPE to repair.

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This item is under embargo until October 22, 2023.