REGULATION OF PROTEIN SYNTHESIS IN THE LACRIMAL GLAND

泪腺对良好的视力至关重要。 泪腺分泌物，包括液体和蛋白质，负责维持角膜的光学表面，保护角膜免受病原体的侵害，并将生长因子输送到角膜，这可能有助于维持眼表的细胞结构。 泪腺分泌功能的激活受神经控制。 然而，该提议的假设是角膜的感觉（传入）神经支配是主要的神经输入，其激活包括中枢和外周自主通路的分泌运动回路。 此外，次要假设是完整的神经回路对于维持泪腺最重要的细胞功能之一是至关重要的，即，蛋白质翻译 在消除感觉激活并使用信息的差异显示后，初步实验已经指出生化缺陷是控制蛋白质翻译起始的激酶eIF2 α的信息和活性的降低。随后的研究表明，虽然基础和反射性泪液减少，泪腺显示对药物刺激的分泌反应升高。 切除或阻断泪腺的副交感神经支配后，将检查消融后观察到的大量分泌颗粒积聚。 翻译过程的其他组成部分也将被检查，泪腺翻译生长因子和分泌蛋白质的信息的能力也将被检查。 据推测，这种不受调节的翻译活性将影响转录因子的产生和不稳定信息的翻译。 拟议的研究将证明神经支配对蛋白质翻译起始的影响，并将寻求了解MAP激酶细胞信号通路的一些关键组分（如Ras）的作用。最后，这表明，泪腺的神经支配状态的异常可能是干眼病的发病机制和衰老过程中泪液蛋白产生的变化的关键因素。

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.