Stimulation of Tear Secretion by a Novel Glycoprotein

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DESCRIPTION (provided by applicant): Dry eye is a ubiquitous, often overlooked, underdiagnosed and poorly understood affliction of the ocular surface. This common opthalmological complaint can markedly affect a patient's quality of life. As a multifactorial disease, dry eye has hyposecretory, auto-immune, inflammatory, hormonal, neurogenic, toxic, and iatrogenic components. Common to all etiologies is a decrease in both volume and quality of tear secretion. Current therapy ranges from topical application of aqueous, oil and gel tear film constituent replacement "artificial" tears, to topical anti-inflammatory drugs, to oral secretagogues. There are currently no approved topical agents indicated for enhancement of tear flow and production, which would address the primary defect in aqueous deficiency dry eye disease. Lacritin is a stable, novel human tear glycoprotein produced solely by lacrimal and salivary glands. It binds to and stimulates a rapid, sustained release of calcium in cultured corneal epithelial cells, which suggests topical application of lacritin may stimulate the cornea/lacrimal gland axis to increase tear production. Based upon these properties elucidated in cell culture, we hypothesize that lacritin has potential as a therapeutic agent to promote tear production. Compared to current therapy, as an ocular-specific prosecretory glycoprotein, lacritin has a unique mechanism of action. We expect that topical application of lacritin will increase tear production by stimulation of the lacrimal gland/corneal axis. The long-term goals of this translational research project are to develop lacritin as an efficacious, nontoxic topical treatment. Specific aims for this proposal are (1) demonstration, using an in vivo rabbit model, of the ability of lacritin to increase tear production after topical administration, (2) determination of the effect of lacritin on the normal composition of tears, and (3) examination of lacritin-treated ocular tissues for signs of adverse effects. The primary outcome measurement is lacritin's ability to increase tear production. In vivo analysis also includes confocal microscopy, slit lamp biomicroscopy, digital photography, application of the MacDonald-Shadduck Scale for Ocular Toxicity, tear break up time, vital dye assessment with fluorescein and Lissamine green, and Schirmer's test for tear production.