Ocular Hyperalgesia in Dry Eye

项目摘要 干眼病(DE)是一种多因素疾病，由泪膜不稳定和 眼睛刺激和视力模糊的症状。症状缓解是DE患者寻求治疗的主要原因 医疗救治。然而，减少眼部炎症迹象的局部眼科治疗往往失败。 处理中重度病例的症状和DE的外周体征不能可靠地预测 疾病的严重性。这些发现表明中枢神经系统机制在发育和发育中起着关键作用。 重症DE患者眼痛的维持；然而，对中枢神经知之甚少 与症状性DE相关的眼部信号的处理。来自以下方面的证据趋同 电生理学、分子和解剖学方法应用于啮齿动物泪液模型。 缺陷性眼眶外腺摘除。该项目的总体目标是确定 持续性撕裂复位术后三叉神经脑干神经元兴奋性增加，如果神经元- 神经胶质细胞的相互作用有助于改变神经处理和增强保护性眼肌反射。 目的1开发一种定量感觉测试(QST)方案来表征编码特性 雄性和雌性大鼠眼部三叉神经脑干神经元。一种新的记录和分析方法， 用来评估眼轮匝肌上部和下部的斜视活动 麻醉大鼠伤害性行为的测量。目标2确定是否存在“前馈”路径 在DE中，三叉神经尾与三叉头区的连接导致眼痛过敏。目标3 确定：a)如果驱动小胶质细胞激活的感觉信号是通过上调Toll样和 嘌呤能P2x受体，b)小胶质细胞的分布和定位神经活性产物(IL-1β， BDNF)及其在神经元和神经胶质细胞上的受体，以及c)阻断神经元与神经胶质细胞的相互作用 假手术组和DE组大鼠眼球反应神经元和诱发眼睑肌肉反应的特点 雌性老鼠。通过将神经记录和眼肌活动与干扰 小胶质细胞激活(嘌呤能受体)、炎性小体形成(NLRP3)及其产物 (IL-1β)，该项目将提供有关眼部高敏感性中枢机制的新信息。 泪液缺乏的动物模型。该项目的长期目标是开发新的方法来 评估中重度DE患者的症状，并确定是否以神经元受体为靶点- 小胶质细胞的相互作用具有治疗DE眼部痛觉过敏的潜力。

Project Summary Dry eye disease (DE) is a multifactorial condition defined by signs of tear film instability and symptoms of ocular irritation and blurred vision. Symptom relief is the primary reason DE patients seek medical attention. However, topical eye treatments that reduce the signs of ocular inflammation often fail to manage symptoms in moderate to severe cases and peripheral signs of DE do not reliably predict disease severity. These findings suggest a critical role for CNS mechanisms in the development and maintenance of ocular pain in severe cases of DE; however, little is known about central neural processing of ocular signals that are relevant for symptomatic DE. Converging lines of evidence from electrophysiological, molecular and anatomical approaches are applied in a rodent model for tear deficiency, exorbital gland removal. The overall goals of this project are to determine mechanisms for increased neural excitability of trigeminal brainstem neurons after persistent tear reduction and if neuron- glia interactions contribute to altered neural processing and enhanced protective eye muscle reflexes. Aim 1 develops a quantitative sensory testing (QST) protocol to characterize the encoding properties of ocular trigeminal brainstem neurons in male and female rats. A novel recording and analysis method is developed to assess squint-like activity in upper and lower portions of the orbicularis oculi muscle as a measure of nociceptive behavior in anesthestized rats. Aim 2 determines if a “feed forward” pathway connecting caudal with rostral trigeminal regions contributes to ocular hyperalgesia in DE. Aim 3 determines: a) if sensory signals that drive microglia activation do so by upregulating Toll-like and purinergic P2x receptors, b) the distribution and localization neuroactive products by microglia (IL-1β, BDNF) and their receptors on neurons and glia, and c) blockade of neuron-glia interactions alter the properties of ocular-responsive neurons and evoked eyelid muscle responses in sham and DE male and female rats. By combining neural recording and eye muscle activity with approaches that interfere with microglia activation (purinergic receptors), inflammasome formation (NLRP3) and products of microglia (IL-1β), this project will provide novel information on central mechanisms of ocular hypersensitivity in an animal model for tear deficiency. The long-term goals of this project are to develop new approaches to assess symptoms in moderate to severe cases of DE and to determine if targeting receptors for neuron- microglia interactions has therapeutic potential to manage ocular hyperalgesia in DE.