Thursday, April 10, 2025
4/10/2025
THE UBIQUITIN PATHWAY IN CORNEAL SCARRING - Project Summary: The ubiquitin pathway in corneal scarring Scarring in the cornea resulting from injury, trauma, or infection can lead to debilitating opacities and permanent vision loss. Acute scarring, similar to chronic fibrosis, is characterized by immune cell infiltration and the persistence of cells termed myofibroblasts. We have found that the deubiquitinase (DUB) USP10 is a key regulator of scarring pathways in the cornea. Knockdown of USP10 in vivo leads to a significant reduction in the development of myofibroblasts, cell apoptosis, the presence of CD45+ immune cells, and fibrotic extracellular matrix in a healing wound. We are proposing to test the central hypothesis that USP10 is a key regulator of myofibroblast persistence in a corneal scar via its multi- factorial role in wound healing. Specifically, since USP10 is a DUB for αv-integrins and p53, in Specific Aim 1 we will unravel the complex role of USP10 in integrin recycling and p53 dynamics in primary human corneal fibroblasts and in mice in vivo. The communication between fibroblasts and macrophages plays a critical role in scarring outcomes. In Specific Aim 2 we will develop novel 3D and 2.5D hydrogel systems with “tunable stiffness” that mimic a 3D environment close to the stiffness of the healing cornea. Using these hydrogels, mouse corneal fibroblasts will be cocultured with mouse bone marrow derived macrophages (M0/M1/M2) to elucidate the role of USP10 in macrophage-mediated myofibroblast development and contraction. In Specific Aim 3 using three separate mouse models we will assess the role of USP10 in immune cell infiltration into a corneal wound.
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