The lacrimal gland is of critical importance to good vision. Lacrimal gland secretions, including fluid and proteins, are responsible for maintaining the optical surface of the cornea, protecting the cornea from pathogens, and conveying growth factors to the cornea, which may help to maintain the cellular structure of the ocular surface. Activation of the secretory function of the lacrimal gland is under neural control. However, it is the hypothesis of this proposal that the sensory (afferent) innervation of the cornea is the primary neural input, which activates a secretomotor circuit comprising central and peripheral autonomic pathways. Moreover, the secondary hypothesis is that the intact neural circuit is critical to the maintenance of one of the most important cellular functions of the lacrimal gland, i.e., protein translation. After eliminating sensory activation and using differential display of message, preliminary experiments have pointed to the biochemical deficit as a decrease in message and activity of a kinase, elF2alpha, which controls the initiation of protein translation. Subsequent studies have shown that although basal and reflex tears are decreased, the lacrimal gland reveals elevated secretory responses to pharmacological stimulation. The massive accumulations of secretory granules seen after this ablation will be examined after removal or blockade of the parasympathetic innervation of the lacrimal gland. Other components of the translation process will also be examined, as will the ability of the lacrimal gland to translate messages for growth factors and secreted proteins. It is hypothesized that this unregulated translational activity will affect the production of transcription factors and the translation of unstable message. The proposed studies will demonstrate the innervational influences on the initiation of protein translation and will seek to understand the role of some key components of the MAP kinase cell signaling pathways, such as Ras. Finally, it is suggested that abnormalities of the innervational status of the lacrimal gland may be a key factor in the pathogenesis of dry eye disease and the changes seen in tear protein production in aging.
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