Wednesday, May 21, 2025
5/21/2025
Decorin mimetics for treating corneal scarring and neovascularization - PROJECT SUMMARY The cornea is continuously subject to insults from the external environment that can lead to stromal scarring and neovascularization, and, consequently, vision loss. Although corneal opacity is a leading cause of sight impairment worldwide, there are limited treatments available for preventing corneal scarring and angiogenesis after corneal injuries. Ultimately, loss of transparency is treated by corneal transplantation; however, corneal angiogenesis in the host cornea is a major risk factor for corneal rejection. Therefore, there is an urgent medical need for alternative treatment options. Decorin is a major ECM component in the cornea that has a central role in regulating collagen fibrillogenesis, as well as, cell behavior via the direct interaction with growth factors and cell surface receptors. Studies have shown that decorin antagonizes TGF-β1 signaling, a central regulatory cytokine in corneal wound healing that promotes ECM deposition and scar tissue formation. Following corneal injury, increased TGF-β1 levels induce keratocyte transdifferentiation into myofibroblasts, and, subsequently, corneal fibrosis (scarring). Moreover, decorin also regulates the physiological balance between pro-and anti-angiogenic factors in the normal and injured cornea via binding to VEGFR2. Decorin binding to VEGFR2 inhibits VEGFA, the natural ligand of VEGFR2, thereby suppressing VEGF signaling, and consequently inhibiting angiogenesis. Decorin deficiency aggravates corneal vascularization, while decorin upregulation, via gene therapy using an adeno- associated virus, successfully inhibits corneal neovascularization in vivo. Therefore, decorin holds great pharmaceutical potential for treating corneal injuries to prevent corneal scarring and neovascularization. This proposal aims to characterize binding interface of decorin:TGFβ1 and decorin:VEGFR2 to engineer novel decorin based drugs that inhibit TGFβ1 (Aim 1) and VEGFR2 (Aim 2) with higher affinity than decorin. Our central hypothesis is that by obtaining in depth mechanistic understanding of the molecular interactions between decorin and its targets we can design decorin-based pharmaceuticals with increased ability to prevent corneal scarring and angiogenesis compared to native decorin and without off-target effects. For such, decorin:TGFβ and decorin:VEGFR2 complexes will be modeled using deep learning computational methods, and decorin based drugs produced by mutagenesis to increase their affinity to TGFβ and VEGFR2. The efficacy of the decorin based drugs for preventing corneal scar formation and pathological neovascularization will be verified using in vitro (Aim 1 and 2) and in vivo assays (Aim 3).
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