U01EY034693

Understanding Neural Control of the Ocular Surface - Project Summary

Currently, our understanding of how the nervous system maintains ocular surface homeostasis is extremely limited. New technologies, methods, and models are needed to advance our scientific understanding and address knowledge gaps.

The ocular surface and tear film-secreting glands, including the lacrimal and meibomian glands, as well as the goblet cells, are carefully controlled to provide an optically smooth, low-scattering surface with appropriate immune and injury responses. Sensory feedback to maintain the structural and functional integrity of the ocular surface is provided by the corneal nerves. These nerves send feedback from stimuli such as chemical, thermal, and mechanical signals to ganglia (e.g., trigeminal) and brain regions (e.g., ventral posteromedial thalamus) to drive the production of tear film components and the blink reflex.

This delicate balance of neural control is disrupted by damage, peripheral neuropathies, inflammation, and further complicated by a wide array of immune responses to various diseases. Dysfunction of this feedback loop can lead to a downward spiral of further dysregulation. Aberrant neural control of the ocular surface can result in abnormal sensation and pain, which in the worst cases can be disabling. To find remedies, it is first essential to understand the underlying neural control system and how it adapts to its environment.

In this proposal, we aim to bring new tools and models to study molecular, cellular, and functional interactions across systems responsible for neural control of the ocular surface. We will examine how these interactions change under different inflammatory and pain conditions. Our team consists of experts across multiple fields, including advanced 3D microscopy, neuroscience, electrophysiology, pain, ocular immunology, ocular lipid metabolism, ocular surface disorders, spatial statistics, and machine/deep learning.

To achieve our goals, we will utilize cutting-edge techniques and technologies, such as optical clearing, tract tracing, ethologically-valid behavior analysis, machine/deep learning, spatial statistics, genetically encoded calcium imaging, light-sheet microscopy, multiplexed 3D fluorescence in situ hybridization (FISH) imaging, and multi-array electrodes implanted in the brain. These tools will help us assess molecular, cellular, and functional interactions across organs and begin to understand ocular surface control at the organism level.

We will also employ several relevant animal models to assess ocular surface control under different inflammatory and pain conditions. These models include AWAT2 deficient mice that mimic evaporative dry eye disease (DED), diabetic mice, an epithelial debridement model with Pseudomonas aeruginosa that mimics bacterial keratitis, and human donor eyes. The mouse models all have GCAMP6F expressed in corneal nerves, allowing functional imaging of calcium transients. With these models, we will study both innate and adaptive immunity, as well as nociceptive and neuropathic pain responses.

In addition, we will apply nerve growth factor (NGF) to our models to study how a potential treatment option alters the ocular surface control system.

Case Western Reserve University

NOT APPLICABLE

93.867 - Vision Research

National Eye Institute (NEI) [HHS - NIH]

Cleveland, Ohio 44106 United States

Single Zip Code

Ocular Surface Innervation from Cell Types to Circuit Functions (U01 Clinical Trial Not Allowed) (RFA-EY-21-004)

Amendment Since initial award the total obligations have increased 385% from $1,444,600 to $7,006,310.