Ocular Hyperalgesia in Dry Eye

干眼症的眼部痛觉过敏

• 批准号: 9364844
• 负责人: DAVID A BEREITER
• 金额: $ 38.35万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9364844
• 关键词: Affect; Analgesics; Anatomy; Animal Model; Animals; Behavior; Blinking; Blurred vision; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Burning Pain; Cervical; Classification; Communication; Complex; Cornea; Development; Disease Progression; Dryness; Electrophysiology (science); Esthesia; Excision; Eye; Eye diseases; Eyelid structure; Female; Fiber; Film; Foreign Bodies; General Population; Gland; Goals; Hyperalgesia; Hypersensitivity; Inflammasome; Inflammation; Interleukin-1 beta; Interruption; Knowledge; Lacrimation; Maintenance; Measures; Mechanics; Methods; Microglia; Modality; Modeling; Molecular; Muscle; Neuroglia; Neurons; Nociception; P2X-receptor; Pain; Pain management; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Population; Process; Property; Protocols documentation; Purinoceptor; Rattus; Reflex action; Rodent Model; Role; Sampling; Sensory; Severity of illness; Signal Transduction; Stimulus; Strabismus; Symptoms; Synapses; System; Testing; Therapeutic; Trigeminal System; Woman; experimental study; eye dryness; feeding; irritation; male; medical attention; men; nerve injury; neuromechanism; novel; novel strategies; ocular pain; ocular surface; receptor; reduce symptoms; relating to nervous system; response; sensory input; somatosensory; symptom management

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.

项目摘要 干眼症（DE）是由泪膜不稳定性和 眼部刺激和视力模糊的症状。 但是，医疗的局部眼睛治疗会减少眼部炎症的迹象 To Manage Symptoms in Moderate to Severate Casses and Peripheral Signs of de de de de de de de some Reliable Indict 疾病的严重程度。 在严重的DE病例中维持眼睛疼痛的眼睛疼痛； 与症状DE相关的眼部信号的处理。 电生理，分子和原子质在啮齿动物模型中应用 缺陷，欧洲腺去除的整体目标是确定机制 持续减少眼泪后，三叉神经脑干神经元的神经脱位能力增加，如果神经元 - 神经胶质相互作用有助于改变神经加工和增强的保护性眼部肌肉反射。 AIM 1开发了定量感觉测试（QST）协议，以表征 男性和雌性大鼠的眼科三叉神经元神经元。 开发用于评估Orbitalis Oculi肌肉上和下部的斜视样活动 麻醉大鼠中的伤害性行为。 连接尾端的三叉神经regeminal Regeminal Recions会导致DE中的眼部超痛觉 确定：a）如果驱动小胶质细胞激活的感觉信号通过上调类似Toll样 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）和神经元和神经胶质的受体，以及c）神经元 - 胶质相互作用的阻滞改变了它们 眼部反应性神经元的特性，并在假男性和DE男性中引起的诱发肌肉反应以及 雌性大鼠。 小胶质细胞活化（珀林皮层组形成（NLRP3））和小胶质细胞的产物 （IL-1β），该项目提供了有关眼部敏感性中心机制的新信息 撕裂的动物模型。 评估中度的症状以确定DE的Casses，并确定是否将受体靶向神经元 小胶质细胞相互作用具有治疗DE中眼痛觉过敏的治疗潜力。