Assessing Photoreceptor Structure and Function in Normal and Diseased Retinae

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ABSTRACT . Vision loss represents a major health issue and can have both inherited and acquired origins. Tools for noninvasive assessment of the human retina have grown at an incredible pace and now afford the opportunity probe structure and function with single-cell resolution. These tools are central to advancing our understanding of the limits of human vision in health and disease as well improving our ability to develop and evaluate novel therapeutic strategies for patients with vision loss. The long-term goal of our research program remains to develop and disseminate sensitive, noninvasive, high-resolution techniques to assess photoreceptor structure and function. Over the past 14 years we have done this in healthy individuals as well as those with a wide range of retinal and systemic diseases. Previously, our focus has been on retinal structure in inherited retinal degenerations, owing to improved understanding of the genetic basis of these conditions and the emergence of novel therapeutic approaches for these conditions. With the advent of adaptive optics (AO) based tools for assessing retinal function we are uniquely positioned to expand our studies and probe the intersection between photoreceptor structure and function in the human retina. As such, the two major goals for this grant period are to evaluate retinal/photoreceptor structure as it applies to therapeutic potential in vision-limiting pathology and quantify the relationship between disruptions in the photoreceptor mosaic and visual resolution. We have assembled a multidisciplinary research team to achieve these goals through the following specific aims: Aim 1) Determine the identity of the remnant cell population in the fovea of individuals with blue cone monochromacy (BCM), Aim 2) Probe the link between cone spacing and AO-corrected acuity in contiguous and disrupted cone mosaics, and Aim 3) Quantify foveal structure and function in individuals with a history of premature birth. The diverse approaches being utilized will provide insight into the link between foveal anatomy, photoreceptor topography, and visual behavior. This work is expected to have a positive clinical impact by filling critical gaps in the literature and providing an enhanced framework for targeting clinical therapies in BCM as well as understanding the impact of prematurity on retinal structure and function. Our proposal addresses research needs, gaps, and opportunities outlined in the 2021-2025 NEI Strategic Plan, “Vision for the Future”: “Explore and exploit connections between biological measurements and theoretical models of visual processes,” “Conduct careful clinical phenotyping to identify quantifiable biomarkers of disease to allow for more accurate diagnosis, risk prediction, and evaluation of treatment efficacy over time,” “Develop and validate imaging methods for identifying clinical disease biomarkers; for enhancing disease diagnosis, classification, and prediction; and for standardizing quantitative metrics among different devices,” and “Expand incentives to validate and share code, develop tools that are readily shared and/or operated in the cloud, and develop best practice guidelines for algorithm validation, documentation, code construction, and commenting.”