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侵害，并向角膜输送生长因子，这可能有助于维持眼表面的细胞结构。泪腺分泌功能的激活是受神经控制的。然而，这一建议的假设是，角膜的感觉（传入）神经支配是主要的神经输入，它激活由中枢和外周自主神经通路组成的分泌运动回路。此外，第二个假设是完整的神经回路对维持泪腺最重要的细胞功能之一至关重要，即蛋白质翻译。在消除感觉激活并使用信息的差异显示后，初步实验指出生化缺陷是控制蛋白质翻译起始的激酶elf2 α的信息和活性降低。随后的研究表明，虽然基底泪和反射泪减少，但泪腺对药物刺激的分泌反应升高。切除或阻断泪腺副交感神经支配后，检查消融后大量分泌颗粒的积聚。翻译过程的其他组成部分也将被检查，如泪腺翻译生长因子和分泌蛋白信息的能力。据推测，这种不受调节的翻译活性会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对蛋白质翻译起始的影响，并将寻求理解MAP激酶细胞信号通路的一些关键成分，如Ras的作用。最后，我们认为泪腺神经状态的异常可能是干眼病发病和衰老过程中泪液蛋白产生变化的关键因素。

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.