Objective
We will meet this need by developing a new preparation of the isolated, perfused mouse eye where we record retinal ganglion cell (RGC) spike responses directly from the optic nerve during visual stimulation. Critically, this preparation leaves the retinal vasculature intact, allowing us to measure and manipulate blood glucose and oxygen and to deliver drugs through the vascular system over the course of hours or even days, all while monitoring the actual neural signals responsible for vision. This technology development project promises to revolutionize the way we measure retinal dysfunction in diabetes and how we search for new treatments.
Background Rationale
Evidence has been mounting over the last two decades that neurodegeneration precedes vascular remodeling in DR, both in animal models and in humans. To bridge the gap between the early neurodegeneration that we now know exists in DR and the clinical management strategies focused on late-stage vascular remodeling, we need an assay where we can measure retinal function directly and with high sensitivity while maintaining experimental control of glucose and oxygen in the retinal vasculature. Our proposed preparation would be the first to meet this challenge.
Description of Project
Diabetic Retinopathy (DR) is one of the most debilitating complications of Type 1 diabetes, affecting around 86% of patients and threatening vision in 42%. DR begins at the molecular level, where excess glucose changes the cellular milieu and induces a number of adaptations, and progresses to the death of vascular cells, compromising the delivery of oxygen and nutrients to the retina, and the death of neurons, compromising vision. DR left untreated can ultimately result in vitreous hemorrhage, retinal detachment, glaucoma, and blindness.
Clinical treatment of DR is in need of new therapeutic approaches based on a more thorough understanding of its early-stage retinal neuropathology. While basic research has pointed to several possible molecular targets, there is currently no sensitive screening platform in an animal model to measure retinal dysfunction in DR or its possible rescue by experimental compounds. Assays in use for translational DR research are insensitive, indirect, unphysiological, or only useful for late-stage disease.
We will meet this need by developing a new preparation of the isolated, perfused mouse eye where we record retinal ganglion cell (RGC) spike responses directly from the optic nerve during visual stimulation.
Anticipated Outcome
The work will be completed in three Aims. We will demonstrate the successful development of the preparation (Aim 1), measure RGC dysfunction in acute hyperglycemia and in a Type 1 diabetes model (Aim 2), and screen candidate compounds for rescue of RGC light responses (Aim 3).
Relevance to T1D
Diabetic Retinopathy (DR) is one of the most debilitating complications of Type 1 diabetes, affecting around 86% of patients and threatening vision in 42%. DR begins at the molecular level, where excess glucose changes the cellular milieu and induces a number of adaptations, and progresses to the death of vascular cells, compromising the delivery of oxygen and nutrients to the retina, and the death of neurons, compromising vision. DR left untreated can ultimately result in vitreous hemorrhage, retinal detachment, glaucoma, and blindness.
Clinical treatment of DR is in need of new therapeutic approaches based on a more thorough understanding of its early-stage retinal neuropathology. While basic research has pointed to several possible molecular targets, there is currently no sensitive screening platform in an animal model to measure retinal dysfunction in DR or its possible rescue by experimental compounds. Assays in use for translational DR research are insensitive, indirect, unphysiological, or only useful for late-stage disease.