Developmental Regulation of Corneal Innervation

角膜神经支配的发育调节

• 批准号: 7579454
• 负责人: THOMAS Frank LINSENMAYER
• 金额: $ 44.9万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579454
• 关键词: 3-Dimensional; Age; Antibodies; Apical; Area; Axon; Belief; Biological Models; Blinking; Brain-Derived Neurotrophic Factor; Cell Communication; Cells; Characteristics; Chemicals; Chickens; Coculture Techniques; Collagen; Confocal Microscopy; Cornea; Corneal Stroma; Corneal Ulcer; Coupled; Data; Development; Down-Regulation; Dyes; Electron Microscopy; Electroporation; Embryo; Embryonic Development; Epithelial Cells; Esthesia; Event; Fluorescence Microscopy; Free Nerve Ending; Ganglia; Gel; Goals; Growth; Human; Immunoelectron Microscopy; Immunofluorescence Immunologic; Infection; Investigation; Keratitis; Label; Laboratories; Laser In Situ Keratomileusis; Lead; Length; Lobe; Mechanics; Mediating; Modeling; Molecular; Monoclonal Antibodies; Myxoid cyst; N-terminal; Nerve; Neurons; Neuropilin-1; Nociceptors; Operative Surgical Procedures; Pain; Play; Population; Preparation; Production; Proteins; Reaction; Regulation; Role; Semaphorin-3A; Sensory; Series; Staging; Stimulus; Structure; Structure of trigeminal ganglion; Surgical complication; Synapses; Synaptic Vesicles; System; Testing; Time; Tissues; Tubulin; Ulcer; Vesicle; Vision; base; chronic pain; corneal epithelium; nerve supply; ophthalmic nerve; promoter; public health relevance; receptor

DESCRIPTION (provided by applicant): The cornea is one of the most densely innervated tissues in the body. Corneal nerves originate chiefly from the ophthalmic branch of the trigeminal ganglion (TGG) and are largely sensory, responding to noxious mechanical, thermal and chemical stimuli by transducing sensations of pain (nociceptors). They are also involved in protecting the cornea from damage by modulating the blinking reaction and increasing the production of tears, and they are required for maintaining the cornea in a healthy state. Thus, pathological conditions that interfere with normal innervation and nerve function can have deleterious consequences, ranging from chronic pain to ulceration and loss of transparency. However, little is known concerning the mechanisms responsible for corneal innervation. The embryonic chicken provides an advantageous developmental model for investigating corneal innervation, as in this species innervation occurs in a series of discrete stages that are temporally and spatially separable from one another. These stages are: (1) the growth and attraction of nerves from the TGG to the cornea, (2) invasion of nerves into the corneal stroma and (3) the formation of branches from the nerves that enter and innervate the corneal epithelium (CE) where they terminate. In the studies to be proposed one of the goals will be to elucidate the mechanism(s) involved in regulating these events. The other area of investigation will be to examine the fate of these nerves once they enter the CE - as this is where sensation occurs. The conventional belief is that these nerves terminate as free nerve endings. However we will examine an alternative, which is that they interact with CE cells in a manner that is structurally and functionally unique to the cornea. PUBLIC HEALTH RELEVANCE The cornea is one of the most densely innervated tissues in the body. These nerves are largely sensory, responding to noxious mechanical, thermal and chemical stimuli by transducing these as sensations of pain. The corneal nerves are also involved in protecting the cornea from damage, by modulating the blinking reaction and increasing the production of tears, and they are also involved in maintaining the cornea in a healthy state. Thus, pathological conditions that interfere with normal innervation and nerve function can have deleterious consequences - ranging from chronic pain , to ulceration, to decreased transparency. For example, a disruption in corneal innervation - as can occur by damage from herpes infection - can result in degenerative neurotrophic keratitis that can produce corneal ulceration and a loss of transparency. Also, following vision corrective surgical procedures (e.g., PRK and LASIK), a decrease in innervation can occur that can lead to post-surgical complications. However, surprisingly little is known concerning the mechanisms responsible for corneal innervation, including those that are involved in embryonic development. For developmental studies of corneal innervation, the embryonic chicken cornea provides an advantageous model which will be used for the proposed studies. In most aspects the chicken cornea is indistinguishable from that of the human. Structurally this cornea has all the layers of the human cornea, and the molecular compositions of these layers are essentially identical to those of the human. In addition, in the embryonic chicken cornea, innervation occurs as a series of discrete stages, each which can be studied separately. Elucidating the cellular and molecular mechanisms that are involved in these different stages of innervation is one of the major goals of the proposed studies. The other major area of investigation will involve how, within the cornea, sensation is transferred to the nerves. The conventional belief is that this involves nerves that terminate within the corneal epithelium as free nerve endings. However, based on recent observation in our laboratory, we will examine an alternative, which is that the endings of the corneal nerves interact with specialized corneal epithelial cells to produce a sensory unit that is structurally and functionally unique to the cornea.

描述(申请人提供)：角膜是人体内神经分布最密集的组织之一。角膜神经主要起源于三叉神经节(TGG)的眼支，主要是感觉神经，通过传递痛觉(伤害性感受器)对有害的机械、热和化学刺激做出反应。它们还通过调节眨眼反应和增加泪水的产生来保护角膜免受损害，而且它们是维持角膜健康状态所必需的。因此，干扰正常神经和神经功能的病理情况可能会产生有害的后果，从慢性疼痛到溃疡和透明度丧失。然而，对角膜神经支配的机制知之甚少。胚胎鸡为研究角膜神经支配提供了一个有利的发育模型，因为在这种物种中，神经支配发生在一系列在时间和空间上相互分离的离散阶段。这些阶段是：(1)从TGG到角膜的神经的生长和吸引；(2)神经侵入角膜基质；(3)从神经进入并支配角膜上皮(CE)的分支的形成。在即将提出的研究中，目标之一将是阐明调控这些事件的机制(S)。另一个调查领域将是检查这些神经进入CE后的命运--因为这是感觉发生的地方。传统观点认为，这些神经以自由神经末梢的形式终止。然而，我们将研究另一种选择，即它们以一种在结构和功能上对角膜独特的方式与CE细胞相互作用。与公众健康相关角膜是人体内神经分布最密集的组织之一。这些神经在很大程度上是感觉神经，通过将这些作为痛感来传递，对有害的机械、热和化学刺激做出反应。角膜神经也参与保护角膜免受损害，通过调节眨眼反应和增加泪水的产生，它们还参与维持角膜的健康状态。因此，干扰正常神经和神经功能的病理情况可能会产生有害的后果--从慢性疼痛到溃疡，再到透明度降低。例如，角膜神经支配的中断--如疱疹感染造成的损害--可能会导致退行性神经营养性角膜炎，从而导致角膜溃疡和透明度丧失。此外，在视力矫正手术(如PRK和LASIK)后，神经支配的减少可能会导致术后并发症。然而，令人惊讶的是，关于角膜神经支配的机制，包括与胚胎发育有关的机制，人们知之甚少。对于角膜神经的发育研究，鸡胚胎角膜提供了一个有利的模型，将被用于拟议的研究。在大多数方面，鸡的角膜与人类的角膜是难以区分的。在结构上，这个角膜有人类角膜的所有层，这些层的分子组成基本上与人类的相同。此外，在鸡胚胎角膜中，神经支配发生在一系列离散的阶段，每个阶段都可以单独研究。阐明参与这些不同神经支配阶段的细胞和分子机制是拟议研究的主要目标之一。另一个主要的研究领域将涉及角膜内感觉是如何传递到神经的。传统的观点认为，这涉及到以游离神经末梢的形式终止于角膜上皮内的神经。然而，根据我们实验室最近的观察，我们将研究一种替代方案，即角膜神经末梢与专门的角膜上皮细胞相互作用，产生结构和功能上独一无二的角膜感觉单位。