Nervous System Mechanisms of Dry Eye

干眼症的神经系统机制

• 批准号: 8047309
• 负责人: Michael L. Oshinsky
• 金额: $ 20.64万
• 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/8047309
• 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. PUBLIC HEALTH RELEVANCE: Dry eye disease afflicts millions of Americans annually and is the most frequent complaint from patients visiting eye care clinics. It also could lead to serious visual disturbances including blindness. We propose to study the corneal afferent mechanisms underlying the tear production reflex and to attempt to establish its relationship to dry eye disease. The results from this study may lead to a new approach to treatments for dry eye disease.

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。它需要一个称为泪液功能单位的综合系统的合作，该系统由眼表组织、分泌腺和神经系统组成，它们共同产生和维持正常的泪膜。任何一组这些成分的紊乱都会导致干眼症。角膜感觉传入是这些成分之一。它们的激活被认为是基础泪液产生的关键，因此它们的功能障碍可能导致长期缺乏泪液，从而导致干眼症。然而，尽管做了大量的工作来表征角膜传入，它们在流泪反射或干眼病中的作用仍然有待确定。最近，我们发现了一种特殊类型的冷敏感角膜神经，它被认为对泪液产生至关重要的各种眼部刺激激活：角膜干燥，温和冷却，泪液蒸发和高渗性泪液。有证据表明，干眼病在某种程度上是检测眼表状况（如角膜冷却和高渗性泪液）的机制功能障碍。因此，我们假设这种特殊类型的角膜传入神经的激活将诱导泪液产生，并且它们的功能障碍有助于干眼病。如果是这样，选择性破坏这些冷敏感的角膜传入应该导致干眼症。 最近的证据表明，神经膜受体（TRPM 8，TRPV 1，TRPA 1）的成员驻留在这种特殊类型的角膜传入参与泪液的产生; TRPM 8受体介导的冷却反应;和TRPV 1/TRPA 1受体介导的高渗反应。我们假设这些受体的激活共同构成了这些冷敏感性角膜传入对角膜干燥的反应，并导致流泪。因此，缺乏这些受体的基因工程突变小鼠应该产生很少的眼泪并表现出干眼症。我们还将表明，这些突变小鼠表现出干眼病的其他体征，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，我们将以化学方法证明一些众所周知的干眼症模型缺乏这些受体，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，拟议的研究将有助于更好地了解催泪反射和干眼病激活的细胞和分子机制，并可能为干眼病的药物治疗提供新的靶点。 公共卫生关系：干眼症每年困扰着数百万美国人，是访问眼科护理诊所的患者最常见的投诉。它还可能导致严重的视觉障碍，包括失明。我们建议研究泪液分泌反射的角膜传入机制，并试图建立其与干眼病的关系。这项研究的结果可能会导致一种新的方法来治疗干眼病。