Tear hyperosmolarity, corneal nerves and dry eye disease

泪液渗透压过高、角膜神经和干眼病

• 批准号: 8792726
• 负责人: Harumitsu Hirata
• 金额: $ 33.99万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792726
• 关键词: Tear; hyperosmolarity; corneal; nerves; dry

DESCRIPTION (provided by applicant): Millions worldwide suffer from the ocular pain and diminished tearing of dry eye disease. Although great advances have been made in many aspects of dry eye research, one area of studies that of corneal nerves has lagged behind. Tear hyperosmolarity is ubiquitously present in dry eye disease and dysfunction of the corneal nerve contributes significantly to the initiation and/or perpetuation of dry eye disease. However, these two subjects have never been studied together. Thus, the proposed research will investigate the effect of tear hyperosmolarity on the corneal nerves responsible for tearing and pain sensation. We recently discovered in rats that special types of corneal nerves displayed many of the response characteristics that are consistent with these nerves serving the functions of tearing and pain sensation. We also discovered that these corneal nerves altered their sensitivities when the eyes were treated with the amounts of hyperosmolar tears found in dry eye patients. Thus, after the corneal nerves were treated with hyperosmolar tears, the nerves began to be excited by a gentle cooling (~1oC) of the cornea, indicating that the normally non-painful stimulus (mild cooling) now activated these neurons presumably giving rise to ocular pain. On the other hand, after the treatment with hyperosmolar tears these neurons began to be less excited by the stimulus thought to be critical for tearing (i.e., drying of the cornea). Therefore, the effects of tear hyperosmolarity on these nerves could explain the exaggerated eye pain and the diminished tearing that DE patients report. We propose to study the following questions in more detail: 1) what is the minimum amount of tear hyperosmolarity necessary to change the neural sensitivity; 2) how long does the tear hyperosmolarity have to remain on the cornea for the nerves to change sensitivity, and does the longer tear hyperosmolarity necessarily lead to more or less activation of these neurons (i.e., more pain and fewer tears?); 3) does the hyperosmolar tear-induced change become permanent, and if so, when? We have also discovered that these neurons show abnormal activity under extended hyperosmolar tear conditions (2 days). What are the mechanisms responsible for these sudden changes in activity? The answers to these questions could identify hyperosmolar tears as being a crucial determinant of the ocular pain and diminished tears found in DE patients. A variety of drugs such as antagonists for inflammatory mediators and membrane ion channels in corneal nerves and epithelia will be tested to block these sensitivity changes and the abnormal activities seen in these nerves. These pharmacological determinations of the changes in corneal nerve functions may lead to better understanding of the pathogenesis of dry eye diseases and offer new avenues of treatment for one of the most common and yet challenging diseases in our society.

描述（由申请人提供）：全世界数以百万计的眼部疼痛和干眼病的撕裂减少。尽管在干眼症研究的许多方面都取得了巨大进步，但角膜神经的研究领域却落后了。撕裂的高渗透性无处不在，在干眼病中存在，角膜神经功能障碍对干眼病的起始和/或永久性造成了显着贡献。但是，这两个主题从未一起研究。因此，拟议的研究将研究撕裂高渗透性对负责撕裂和疼痛感觉的角膜神经的影响。我们最近在大鼠中发现，特殊类型的角膜神经表现出许多与这些神经相一致的反应特征，这些神经具有撕裂和疼痛感的功能。我们还发现，当眼睛用干眼症患者发现的高质量泪水量处理时，这些角膜神经会改变其敏感性。因此，在角膜神经用高颜色的撕裂处理后，角膜的温和冷却（〜1oC）开始激发神经，表明正常无pain的刺激（温和冷却）现在激活了这些神经元，可能会引起这些神经元眼痛。另一方面，在用高渗透撕裂治疗后，这些神经元开始对被认为对撕裂至关重要的刺激（即角膜干燥）的兴奋。所以， 泪液高色对这些神经的影响可以解释夸张的眼睛疼痛以及DE患者报告的撕裂。我们建议更详细地研究以下问题：1）改变神经敏感性所需的最小撕裂高渗透量是多少； 2）撕裂高渗透性必须保留在角膜上以改变灵敏度，而较长的撕裂高渗透性一定会导致这些神经元的激活或多或少会导致这些神经元的激活（即更多的疼痛和更少的眼泪？）； 3）高摩尔泪液引起的变化是否变为永久性，如果是，何时？我们还发现，这些神经元在延长的高摩尔泪液条件下显示出异常的活性（2天）。这些机制是什么原因导致了活动的突然变化？这些问题的答案可以确定高摩尔泪是眼部疼痛的关键决定因素，并且在DE患者中发现了泪水减少。将测试各种用于炎症介质和膜离子通道等多种药物 这些神经。这些对角膜神经功能变化的药理确定可能会更好地理解干眼疾病的发病机理，并为我们社会中最常见，最具挑战性的疾病之一提供新的治疗途径。