Grants We Funded

Abstract

Project Summary: Vision relies on corneal clarity. Limbal stem cells (LSCs), the source of corneal epithelial cells, interact with corneal sensory nerves which stimulate LSC activity. Loss of corneal nerves causes Neurotrophic Keratopathy (NK), hallmarked by corneal ulcers, scarring, and opacification, leading to blindness. Nerve growth factor (NGF) is believed to regulate innervation-dependent epithelial renewal via a yet unknown mechanism. However, NGF lacks consistency and efficacy in NK. Previous studies demonstrate that NGF-induced proliferation and maintenance of cultured human LSCs, which express both NGF receptors (TrkA and p75NTR). We reported that nerve-associated Schwann cells (SCs) as an essential regulatory component of the limbal niche and suggested that NGF released by SCs binds LSCs. This supported the hypothesis that NGF signaling is involved in the regulation of corneal epithelial renewal that occurs via the regulation of LSCs. Innovation: We combined surgical manipulations and cellular molecular biology approaches to determine the cellular source(s) and the mechanisms of NGF signaling, regulating LSC activity. First, we developed an NK animal model in which we rescued corneal clarity by surgically introducing a distinct population of donor nerves into denervated corneas, underscoring the critical role of corneal innervation in epithelial renewal. Second, by studying cells populating the LSC niche and their transcriptional profiles, we introduced a conceptual model of paracrine interactions between SCs and LSCs that involved NGF. Here we will define the extent and the significance of NGF receptors TrkA and p75NTR in corneal epithelial renewal and their antagonistic activity in regulation of LSC activity. We will test the therapeutic modulation of these NGF receptors, aiming to amplify NGF's efficacy in treating NK. We will test the outcomes of a comprehensive strategy that combines more efficacious NGF therapy with corneal neurotization. It represents a pioneering approach in the treatment of advanced-stage Neurotrophic Keratopathy. Summary: This research aims to elucidate NGF signaling in limbal stem cell (LSC) activity for corneal renewal. The study will systematically evaluate the therapeutic potential of NGF, its receptors, and other ligands in Neurotrophic Keratopathy (NK). Pioneering a novel approach, the integration of these ligands with corneal neurotization seeks to develop a comprehensive treatment for advanced-stage NK.

Impact Statement: Loss of corneal nerves can lead to Neurotrophic Keratopathy (NK), causing ulcers, scarring, and blindness. Current treatments lack a cure, allowing NK to progress. Efforts for nerve regrowth include nerve growth factor (NGF) and "corneal neurotization." While promising in early NK, they struggle in advanced cases. NGF, the sole FDA approved growth factor, is ineffective for over 30%, driving ongoing research for a complete cure. NGF's challenge in NK results from limited understanding. This study targets NGF's mechanisms and receptors, TrkA and p75NTR, enhancing NGF's effectiveness. Combining improved NGF with corneal neurotization is a novel NK treatment strategy. This knowledge opens paths for comprehensive NK therapies, potentially enhancing treatment efficacy and outcomes.

Biography
Dr. Borschel is the Chief of Plastic Surgery at Riley Hospital for Children, Indiana University, specializing in pediatric nerve injuries, corneal neurotization, facial paralysis, congenital hand surgery, and microvascular reconstruction. His clinical work focuses on pediatric facial paralysis, nerve injuries, hand surgery and microvascular reconstruction, and he has pioneered corneal neurotization, a treatment for neurotrophic keratopathy, a rare cause of blindness caused by lack of nerve supply to the cornea. His research laboratory focuses on ways to enhance peripheral nerve regeneration, including drug and growth factor delivery, electrical stimulation, and the cellular and molecular mechanisms underpinning neurotrophic keratopathy and corneal neurotization. Dr. Borschel's clinical work and research have significantly contributed to the field, with over 130 publications and leadership roles in professional societies, including President of the American Society for Peripheral Nerve. His research has received support from various funding agencies, and he has received prestigious awards for his contributions to surgery and academic excellence.