Structure and Function of Ocular Lacritin

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Our entirely rewritten application addresses the lacrimal/corneal axis as a fundamental regulator of ocular health. We seek a global understanding of how lacrimal acinar cell secretory control is governed and downstream consequences. Modulation of basal and reflex tear secretion is complex, largely unexplored and reversible; and plays into the enigmatic etiology of Dry Eye syndromes for which basal and reflex tearing capacity is often differentially deficient. Underlying main lacrimal gland 'basal' and 'reflex' tearing (terms that describe output at the ocular surface) are the acinar cell 'constitutive', 'constitutive-like', 'minor regulated' (basal) as well as 'major regulated' (reflex) secretory pathways - each with particular characteristics defined for the most part in other exocrine organs such as the parotid. Hypothetically possible is a receptor-mediated autocrine feedback loop(s) in which secretory product(s) released from one secretory pathway enhance or diminish secretion from another pathway, a potentially sensitive arrangement offering a novel framework for studying lacrimal hyposecretion in Dry Eye. Recently we discovered lacritin, an autocrine enhancer of lacrimal acinar cell basal secretion (Sanghi et al, J. Mol. Biol. '01; cover issue). Lacritin is highly conserved and released from lacrimal acinar cells by the major regulated pathway. It enhances basal tear secretion in a dose dependent manner, and rapidly activates both low amplitude calcium signaling and tyrosine phosphorylation. Lacritin also promotes the proliferation of downstream ductal cells and calcium signaling by corneal epithelial cells. Estimated cell binding affinity is 0.03 - 0.07 nM (versus NGF [0.01 - 1 nM], EGF [0.2 nM], PDGF [0.4 - 0. 7 nM]). Expression studies suggest that the lacritin gene is one of the most lacrimal gland-specific described. Our working hypothesis is that lacritin release stimulates the minor regulated pathway in a G -protein coupled receptor dependent manner, and that ligation of the same receptor in ductal and corneal epithelial cells regulates cell turnover. Our specific aims are therefore: (1) to identify and characterize how lacritin contacts target cell surfaces, (2) to clarify the identity of the lacritin-dependent secretory pathway, its mechanism of activation and significance, and (3) to elucidate lacritin's downstream ductal and ocular surface role.