Molecular and Cellular Aspects of Corneal Nerve Regeneration

描述(申请人提供)：角膜神经功能障碍形成眼部疾病的病理生理学基础，如神经营养性角膜炎和干眼病。眼科手术，如角膜移植和激光辅助原位角膜磨镶术，会横断角膜神经，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优先需求。这项建议建立在我们在K08获奖期间产生的研究成果的基础上。我们的关键发现是，Sema7a促进了角膜中的神经再生，并导致髓样细胞的渗透。我们建议探索我们的假设，即Sema7a作用于神经突起并渗透到角膜中的未成熟髓系细胞(我们称为YFP-MDSCs)，以促进神经再生，从而连接神经元和髓系系统。我们将确定渗透到角膜的髓系细胞的神经营养作用的机制，以及Sema7a如何影响它们的作用(目标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，以便对神经突起和髓样细胞起旁分泌作用(目标B)。最后，我们将确定跨越Sema7a整合素和去整合素基序的多肽是否选择性地影响轴突生长和髓系细胞功能(目标C)。这项建议中详细的研究将产生新的知识，以帮助填补目前我们在理解角膜神经再生机制及其分子和细胞相互作用方面存在的空白，这可能会导致新的治疗方法。

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.