The avascular cornea is innervated by a dense network of sensory processes derived from the ophthalmic and
maxillary regions of the trigeminal ganglion. Corneal nerves provide not only mechanical, chemical, and thermal
sensitivity to the front of the eye but also release nutrients and trophic factors that supply the cornea. Structural
and functional nerve abnormalities are the hallmarks of neurotrophic keratopathy, a degenerative disease
associated with impaired corneal healing and ulceration. These abnormatilies can also be observed in other
conditions known to cause corneal damage, such as dry eye. Most therapeutic approaches aimed to promote
corneal nerve regeneration focus on providing neurotrophic support. Recently, the U.S. Food and Drug
Administration has approved the use of recombinant nerve growth factor eye drops for the treatment of
neurotrophic keratopathy, but its use has been associated with several adverse effects and limitations.
This proposal centers on a major gap in our understanding of the inhibitory mechanisms hampering corneal
nerve regeneration, which could prove important to develop new strategies to promote functional reinnervation.
Research during the last decade has consistently found increased levels of the carbohydrate-binding protein
galectin-3 in the tear fluid and corneal epithelium of patients with ocular surface disease. Importantly, the areas
where increased galectin-3 expression has been observed coincide with the location of intraepithelial nerve
terminals and the basal nerve plexus. It is become increasingly clear that multimerization of galectin-3 leads to
cross-linking of carbohydrate ligands and the formation of lattice-like structures on plasma membranes essential
for regulating cell survival or degeneration. We hypothesize that overabundance of galectin-3 promotes
degenerative signaling by interacting with specific surface receptors in peripheral sensory neurons and may
constitute an important therapeutic target for the full recovery of nerve sensation in corneal disease.
The following specific aims will address this objective: (1) to examine the role of galectin-3 in modulating
neurotrophic signaling, (2) to determine the impact of galectin-3 on the neural mechanisms underlying corneal
disease, and (3) to investigate whether whether therapeutic inhibition of galectin-3 improves corneal nerve
regeneration and sensation. It is anticipated that the successful conclusion of this project will reveal a novel
mechanism by which galectin-3 regulates neurotrophic signaling in corneal nerves. Results could potentially
advance the field of corneal nerve regeneration by targeting the pathological actions of galectin-3 and lead to
the development of novel therapies to promote functional innervation.