The mechanisms underlying posterior capsular opacification

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Extracapsular cataract surgery has greatly reduced the global burden of cataract-related blindness. While this procedure is very effective, most patients develop significant ocular inflammation after cataract surgery, which can compromise vision, while its treatment with potent anti-inflammatory drugs is unpleasant for patients and can cause side effects. While some inflammatory pathways activated by cataract surgery are known, these have not been comprehensively profiled and their mechanisms of pathway induction are not known. Further, optimal implantation of a replacement intraocular lens requires preservation of most of the lens capsule, the basement membrane surrounding the lens. Since lens epithelial cells (LECs) are tightly attached to the lens capsule, not all LECs can be removed during cataract surgery, and these cells tend to undergo robust wound healing responses. The resulting proliferation, migration, transdifferentiation to myofibroblasts, and formation of aberrant lens fibers often results in the formation of opaque plaques in the visual axis post-cataract surgery, resulting in posterior capsular opacification (PCO), a common side effect of cataract surgery. While it is known that myofibroblast formation in PCO requires the activation of TGFβ/SMAD pathways post-surgery, there is a lag between the time of surgery and TGFβ pathway activation, likely due to the need to both activate latent TGFβ, and to prime LECs to efficiently respond to this signaling. However, little is known about the pathways triggered immediately after surgery that lead to robust activation of TGFβ signaling necessary to form fibrotic PCO in vivo. This application seeks to fill these knowledge gaps by investigating the molecular changes that occur in LECs prior to the onset of robust TGFβ pathway activation in two specific aims. The first aim investigates both the molecular mechanisms regulating ocular inflammation post-cataract surgery and the subsequent onset of pro-fibrotic gene expression in the LECs remaining behind after surgery while investigating how this remodeling of the the lens epithelial cell transcriptome is regulated by "immediate early genes“ (IEGs). The second aim tests the hypothesis that the canonical Wnt signaling that upregulates during the first day after cataract surgery is functionally important in the pathogenesis of PCO and investigates its regulation by IEGs. This investigation will fill the current gap in knowledge concerning the molecular changes that occur between the time of surgery and robust TGFβ pathway activation leading to PCO, a major side effect of modern cataract surgery.