Molecular and Cellular Aspects of Corneal Nerve Regeneration

描述（申请人提供）：角膜神经功能障碍是神经营养性角膜炎、干眼病等眼部疾病的病理生理基础。眼科手术如角膜移植术和激光辅助原位角膜磨砂术会破坏角膜神经，并可能导致其功能障碍。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。这个建议是基于我们在K08奖励期间的研究成果。我们的主要发现是Sema7a促进角膜的神经再生并引起骨髓细胞的浸润。我们建议探索我们的假设，即Sema7a作用于神经突和浸润角膜中的未成熟髓样细胞（我们称之为YFP-MDSCs）以促进神经再生，从而连接神经元和髓样系统。我们将确定骨髓细胞浸润角膜的神经营养作用机制以及Sema7a如何影响其作用（Aim A）。我们将确定角膜细胞膜结合的Sema7a是否在细胞外基质中脱落，以对神经突和髓细胞产生旁分泌作用（Aim B）。最后，我们将确定跨越Sema7a整合素和解体素基序的肽是否选择性地影响神经突生长和髓细胞功能（Aim C）。本提案中详细的研究将产生新的知识，以帮助填补目前在我们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.