Developmental Regulation of Corneal Innervation

描述（由申请人提供）：角膜是体内神经支配最密集的组织之一。角膜神经主要起源于三叉神经节（TGG）的眼分支，并且主要是感觉性的，通过传递疼痛感觉（伤害感受器）来响应有害的机械、热和化学刺激。它们还通过调节眨眼反应和增加眼泪的产生来保护角膜免受损伤，并且它们是维持角膜处于健康状态所必需的。因此，干扰正常神经支配和神经功能的病理状况可能具有有害后果，从慢性疼痛到溃疡和透明度丧失。然而，很少有人知道有关的机制负责角膜神经支配。鸡胚为研究角膜神经支配提供了一个有利的发育模型，因为在该物种中，神经支配发生在一系列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，和（3）从进入并支配角膜上皮（CE）的神经的分支的形成，在那里它们终止。在拟进行的研究中，目标之一将是阐明参与调节这些事件的机制。研究的另一个领域将是检查这些神经一旦进入CE的命运-因为这是感觉发生的地方。传统的观点认为，这些神经终止于游离神经末梢。然而，我们将研究一种替代方法，即它们以角膜特有的结构和功能方式与CE细胞相互作用。角膜是人体内神经支配最密集的组织之一。这些神经主要是感觉神经，对有害的机械、热和化学刺激作出反应，将这些刺激转换为疼痛感觉。角膜神经还参与通过调节眨眼反应和增加泪液的产生来保护角膜免受损伤，并且它们还参与维持角膜处于健康状态。因此，干扰正常神经支配和神经功能的病理状况可能具有有害后果-从慢性疼痛到溃疡，再到透明度降低。例如，角膜神经支配的破坏-如可能由疱疹感染引起的损伤-可导致退行性神经营养性角膜炎，其可产生角膜溃疡和透明度丧失。此外，在视力矫正外科手术（例如，LASIK和LASIK），可能发生神经支配的减少，这可能导致术后并发症。然而，令人惊讶的是，很少有人知道有关的机制负责角膜神经支配，包括那些参与胚胎发育。对于角膜神经支配的发育研究，胚胎鸡角膜提供了一个有利的模型，将用于拟议的研究。在大多数方面，鸡角膜与人角膜是无法区分的。在结构上，这种角膜具有人类角膜的所有层，并且这些层的分子组成基本上与人类的分子组成相同。此外，在鸡胚角膜中，神经支配是作为一系列离散的阶段发生的，每个阶段都可以单独研究。阐明神经支配的这些不同阶段所涉及的细胞和分子机制是所提出的研究的主要目标之一。另一个主要的研究领域将涉及如何在角膜内，感觉被转移到神经。传统观点认为，这涉及终止于角膜上皮内的神经作为游离神经末梢。然而，根据我们实验室最近的观察，我们将研究一种替代方法，即角膜神经的末梢与专门的角膜上皮细胞相互作用，产生一种结构和功能上独特的角膜感觉单位。

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.