Developmental Regulation of Corneal Innervation

角膜神经支配的发育调节

• 批准号: 7752507
• 负责人: THOMAS Frank LINSENMAYER
• 金额: $ 45.37万
• 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/7752507
• 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（由申请人提供）：角膜是体内最密集的组织之一。角膜神经主要源于三叉神经节（TGG）的眼科分支，在很大程度上是感觉的，通过传播疼痛的感觉（伤害感受器）来应对有害的机械，热和化学刺激。他们还通过调节闪烁的反应并增加眼泪的产生来保护角膜免受损害，并且它们是将角膜保持在健康状态所必需的。因此，干扰正常神经和神经功能的病理条件可能会带来有害的后果，从慢性疼痛到溃疡和透明度的丧失。但是，关于负责角膜神经的机制知之甚少。胚胎鸡提供了一个有利的发育模型来研究角膜神经，因为在该物种上，在一系列离散的阶段发生，这些阶段在时间和空间上可以彼此分离。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）（3）从进入和支配它们终止的角膜上皮（CE）的神经中的分支形成。在提出的研究中，目标之一将是阐明调节这些事件的机制。研究的另一个领域将是一旦进入CE的神经的命运 - 因为这是感觉的地方。传统的信念是，这些神经终止是自由的神经末日。但是，我们将检查一种替代方案，即它们以结构和功能在角膜在功能上独有的方式与CE细胞相互作用。公共卫生相关性角膜是体内最密集的组织之一。这些神经在很大程度上是感觉的，通过将这些刺激作为疼痛的感觉来响应有害的机械，热和化学刺激。角膜神经还通过调节闪烁的反应并增加眼泪的产生来保护角膜免受损伤，并且它们还参与将角膜保持在健康状态。因此，干扰正常神经和神经功能的病理条件可能会带来有害后果 - 从慢性疼痛，溃疡到透明度降低。例如，角膜神经神经的破坏 - 可能因疱疹感染而造成的损害可能导致退行性神经营养性角膜炎，这会导致角膜溃疡和透明度的丧失。同样，遵循视力纠正手术程序（例如PRK和LASIK），可能会导致神经的减少，这可能导致手术后并发症。但是，关于负责角膜神经的机制，包括参与胚胎发育的机制，知之甚少。对于角膜神经的发育研究，胚胎鸡角膜提供了一种有利的模型，该模型将用于拟议的研究。在大多数方面，鸡肉角膜与人的角膜没有区别。从结构上讲，这种角膜具有人角膜的所有层，这些层的分子组成与人的分子组成基本相同。另外，在胚胎鸡角膜中，神经是一系列离散阶段的发生，每个阶段都可以单独研究。阐明与这些不同神经不同阶段有关的细胞和分子机制是拟议研究的主要目标之一。其他主要调查领域将涉及角膜内的感觉如何转移到神经上。传统的信念是，这涉及神经在角膜上皮内终止为自由神经末端。但是，根据我们实验室的最新观察结果，我们将检查一种替代方案，即角膜神经的结尾与专门的角膜上皮细胞相互作用，以产生一个在结构和功能上具有角膜独特的感觉单元。