Molecular and Cellular Aspects of Corneal Nerve Regeneration

描述（由申请人提供）：角膜神经功能障碍是眼部疾病（如神经营养性角膜炎和干眼病）的病理生理学基础。眼科手术如角膜移植术和激光辅助原位角膜磨镶术会切断角膜神经，并可能导致其功能障碍。负责角膜神经再生的机制尚未完全确定，它们构成了眼科领域的高度优先需求。本提案基于我们在K 08授予期间产生的研究成果。我们的关键发现是Sema 7a促进角膜神经再生并导致骨髓细胞浸润。我们建议探索我们的假设，即Sema 7a作用于角膜中的神经突和浸润的未成熟骨髓细胞（我们称之为YFP-MDSC）以促进神经再生，从而连接神经元和骨髓系统。我们将确定浸润角膜的骨髓细胞的神经营养作用的机制以及Sema 7a如何影响它们的作用（目的A）。我们将确定角膜细胞膜结合的Sema 7a是否在细胞外基质中脱落以用于对神经突和骨髓细胞的旁分泌作用（Aim B）。最后，我们将确定跨越Sema 7a的整联蛋白和去整联蛋白基序的肽是否选择性地影响神经突生长和骨髓细胞功能（Aim C）。本提案中详细介绍的研究将产生新的知识，以帮助填补我们目前对角膜神经再生机制及其分子和细胞相互作用的理解中存在的空白，这可能导致新的治疗方法。

DESCRIPTION (provided by applicant): Corneal nerve dysfunction forms the pathophysiological basis of ocular diseases, such as neurotrophic keratitis and dry-eye disease. Ophthalmic surgical procedures such as keratoplasty and laser-assisted in situ keratomileusis transect corneal nerves and may cause their dysfunction. The mechanisms responsible for corneal nerve regeneration have yet to be fully determined, and they constitute a high-priority need in the field of Ophthalmology. This proposal builds upon our research findings generated during the K08 award period. Our key finding was that Sema7a promotes nerve regeneration in the cornea and causes infiltration of myeloid cells. We propose to explore our hypothesis that Sema7a acts on neurites and infiltrating immature myeloid cells (which we call YFP-MDSCs) in the cornea to promote neuroregeneration, thus linking neuronal and myeloid systems. We will determine the mechanism of neurotrophic actions of myeloid cells that infiltrate the cornea and how Sema7a affects their actions (Aim A). We will determine whether corneal cell membrane- bound Sema7a is shed in the extracellular matrix for paracrine actions on neurites and myeloid cells (Aim B). Finally, we will determine whether peptides spanning integrin and disintegrin motifs of Sema7a selectively affect neurite growth and myeloid cell function (Aim C). Investigations detailed in this proposal will generate new knowledge to help fill gaps that currently exist in our understanding of corneal nerve regeneration mechanisms and their molecular and cellular interactions which may lead to new therapies.