Nervous System Mechanisms of Dry Eye

干眼症的神经系统机制

• 批准号: 8300071
• 负责人: Michael L. Oshinsky
• 金额: $ 20.55万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300071
• 关键词: American; Animal Model; Biological Markers; Blindness; Caring; Characteristics; Chronic; Clinic; Conjunctival Epithelium; Cornea; Deformity; Development; Engineering; Exhibits; Eye; Eye diseases; Film; Functional disorder; Genetic; Gland; Inflammation; Inflammation Mediators; Lacrimal gland structure; Lacrimation; Lead; Left; Limb structure; Maintenance; Mediating; Membrane; Modeling; Molecular; Morphology; Mus; Mutant Strains Mice; Nerve; Nerve Block; Nervous system structure; Neurons; Patients; Pharmacological Treatment; Physiological; Preparation; Production; Property; Rattus; Receptor Activation; Reflex action; Reporting; Research; Role; Sensory; Stimulus; Surface; Symptoms; System; TRPV1 gene; Thermoreceptors; Tissues; Transgenic Mice; Vision; Visit; Visual; Work; conjunctiva; corneal epithelium; evaporation; eye dryness; iodoresiniferatoxin; lacrimal; member; mouse model; novel strategies; ocular surface; receptor; response

DESCRIPTION (provided by applicant): A healthy moist ocular surface is essential for proper visual functioning. It requires cooperation of an integrated system called the Lacrimal Functional Unit, which consists of the ocular surface tissues, secretory glands, and the nervous system, that together produce and maintain a normal tear film. A disturbance in any group of these components leads to dry eye. The corneal sensory afferents are one of these components. Their activation is considered to be critical to basal tear production, and thus their dysfunction could cause a chronic lack of tears, resulting in dry eye. However, despite a great amount of work done to characterize the corneal afferents, their roles in the lacrimation reflex or dry eye disease still remain to be determined. Recently, we identified a special type of cold-sensitive corneal nerve that is activated by a variety of ocular stimulations thought to be critical for tear production: drying of the cornea, gentle cooling, tear evaporation, and hyperosmolar tears. Evidence indicates that dry eye disease is in part a dysfunction of the mechanisms that detect ocular surface conditions such as cooling of the cornea and the hyperosmolar tears. Thus, we hypothesize that activation of this special type of corneal afferent will induce tear production and their dysfunction contributes to dry eye disease. If so, a selective destruction of these cold-sensitive corneal afferents should lead to dry eye. Recent evidence indicates that members of the nerve membrane receptors (TRPM8, TRPV1, TRPA1) reside in this special type of corneal afferent involved in tear production; that TRPM8 receptors mediate the cooling response; and TRPV1/TRPA1 receptors mediate the hyperosmolar response. We hypothesize that activation of these receptors together constitutes the responses of these cold-sensitive corneal afferents to drying of the cornea and leads to tearing. Thus, genetically engineered mutant mice specifically lacking these receptors should produce very few tears and exhibit dry eye. We will also show that these mutant mice display other signs of dry eye diseases such as inflammation of the ocular surface, which would damage the integrity of the ocular surface tissues, producing the abnormal morphology of the corneal and the conjunctival epithelia. Finally, we will demonstrate immunohistochemically that some well-known models of dry eye disease lack these receptors, implying that this fact is one reason that they have dry eye. If the aims of these studies are achieved, the proposed research will lead to a better understanding of the cellular and molecular mechanisms underlying the activation of the lacrimation reflex and dry eye disease, and may provide new targets for pharmacological treatments for dry eye diseases.

描述（由申请人提供）：健康湿润的眼表对正常的视觉功能至关重要。它需要一个被称为泪道功能单元的综合系统的合作，该系统由眼表组织、分泌腺和神经系统组成，它们共同产生并维持正常的泪膜。这些成分中的任何一组受到干扰都会导致干眼症。角膜感觉传入神经是这些组成部分之一。它们的激活被认为对基础泪液的产生至关重要，因此它们的功能障碍可能导致慢性泪液缺乏，从而导致干眼症。然而，尽管已经做了大量的工作来描述角膜传入事件的特征，但它们在流泪反射或干眼病中的作用仍有待确定。最近，我们发现了一种特殊类型的冷敏感角膜神经，它被各种眼部刺激激活，这些刺激被认为对泪液的产生至关重要：角膜干燥、温和冷却、泪液蒸发和高渗透性泪液。有证据表明，干眼病在一定程度上是检测角膜冷却和高渗性泪液等眼表状况机制的功能障碍。因此，我们假设这种特殊类型的角膜传入神经的激活会诱导泪液产生，其功能障碍会导致干眼症。如果是这样，选择性地破坏这些对冷敏感的角膜传入神经会导致干眼症。最近的证据表明，神经膜受体（TRPM8, TRPV1, TRPA1）的成员位于这种特殊类型的角膜传入神经中，参与泪液的产生；TRPM8受体介导冷却反应；TRPV1/TRPA1受体介导高渗反应。我们假设这些受体的激活共同构成了这些冷敏感角膜传入神经对角膜干燥的反应，并导致撕裂。因此，缺乏这些受体的基因工程突变小鼠应该很少流泪并表现出干眼症。我们还将表明，这些突变小鼠表现出干眼病的其他迹象，如眼表炎症，这将损害眼表组织的完整性，产生角膜和结膜上皮的异常形态。最后，我们将用免疫组织化学方法证明一些众所周知的干眼病模型缺乏这些受体，这意味着这一事实是他们患有干眼症的原因之一。如果这些研究的目的得以实现，将有助于更好地了解泪反射激活和干眼病的细胞和分子机制，并可能为干眼病的药物治疗提供新的靶点。