Correlations of structure and function in regenerating corneal nerves

摘要/项目摘要 角膜神经创造了体内最密集的感觉网络，并为角膜提供营养支持 上皮组织。三种类型的模式构成了整个角膜神经种群，并传达离散的 通过对角膜表面的各种刺激做出反应而产生的感觉。角膜损伤很常见，而且 可能是多种原因的结果，从手术干预到代谢紊乱。虽然 角膜神经在损伤后能够再生，其结构完整性经常被破坏，并与 感觉、疼痛和上皮愈合不良的时间延长。三者的特定功能恢复 损伤后的神经亚型在很大程度上仍不清楚，因此限制了对患者治疗结果的两种预测。 以及有效疗法的设计。这项建议的第一个目标是调查结构和 急性角膜损伤再生后角膜神经形态的功能变化。这将是 通过结合体内细胞外电生理学来实现，这是一种高度敏感的技术，可以记录 单个神经元的电活动，用神经成像、免疫组织化学和分子技术。 建议的治疗角膜神经损伤的方法已被证明能促进更快更广泛的生长。 在体外和体内的神经。然而，人们对这些治疗方法的作用后果知之甚少 神经元活动。神经损伤的有效治疗方法必须确保完全神经功能的再生， 保持适当的刺激物检测阈值，同时避免痛苦的失火。血管内皮生长因子，一种内源性 分子在角膜损伤后表达，是治疗角膜损伤的候选药物。尽管它一直是 在角膜损伤后的动物模型中，当补充时被证明具有前神经效应，功能性的 应用血管内皮细胞生长因子的结果还没有确定。该提案的第二个目标将使用 电生理、免疫组织化学、成像和分子技术研究结构 以及血管内皮生长因子治疗对角膜神经亚型恢复的功能影响。 总之，这项研究将阐明再生的角膜神经亚型的功能，并将 首次测试了作为角膜神经修复潜在疗法的血管内皮生长因子的功能影响。 这个项目将由伊利诺伊大学芝加哥分校(UIC)的一名博士/博士生进行，该大学是芝加哥大学的专业 公立研究型大学，在眼科和视觉科学系中排名第一。会是 在对神经元再生的结构和功能后果的评估方面独一无二 经典的分子方法和灵敏的角膜神经活性检测技术。该中心的培训目标是 该项目旨在发展对神经学主题感兴趣的初出茅庐的内科科学家的职业生涯。 眼科的再生。该奖学金项目将由一个团队的专家指导，该团队包括 一位来自UIC和威尔·康奈尔大学的领先角膜内科医生、科学家和电生理学家。

ABSTRACT/PROJECT SUMMARY Corneal nerves create the densest sensory network in the body and provide trophic support to the corneal epithelium. Three types of modalities constitute the overall corneal nerve population and convey discrete sensations by responding to various stimulations of the corneal surface. Damage to the cornea is common and can be the consequence of diverse causes, ranging from surgical interventions to metabolic disorders. Although corneal nerves are able to regrow after injury, their structural integrity is frequently disrupted and associated with prolonged changes in sensation, pain, and poor epithelial healing. The specific functional recovery of the three nerve subtypes after injury is still largely unknown, thus limiting both predictions of patient treatment outcomes and design of effective therapeutics. The first objective of this proposal is to investigate the structural and functional changes in the corneal nerve modalities after regeneration from acute corneal injury. This will be achieved by combining in vivo extracellular electrophysiology, a highly sensitive technique that records the electrical activity of a single neuron, with nerve imaging, immunohistochemical, and molecular techniques. Proposed therapeutics for corneal nerve injuries have been shown to promote faster and more extensive growth of nerves both in vitro and in vivo. However, little is known about these treatments’ functional consequences on neuronal activity. Effective therapeutics for nerve injury must ensure regeneration of full neural functionality, maintaining proper thresholds for irritant detection while avoiding painful misfiring. VEGF, an endogenous molecule expressed in the cornea post injury, is a candidate therapeutic for corneal injuries. Although it has been shown to have pro-neural effects when supplemented in animal models after corneal damage, the functional outcomes of VEGF application have not been characterized. The second objective of this proposal will use electrophysiological, immunohistochemical, imaging, and molecular techniques to investigate the structural and functional consequences of treatment with VEGF on the recovery of corneal nerves subtypes. Overall, this study will elucidate the functionality of the regenerated corneal nerve subtypes and will be the first to test the functional impacts of VEGF as a potential therapy for corneal nerve repair. This project will be conducted by an MD/PhD student at the University of Illinois-Chicago (UIC), Chicago’s major public research university, within the top-ranked Department of Ophthalmology and Visual Sciences. It will be unique in its assessment of both structural and functional consequences of neuronal regeneration by combining classical molecular methods with a sensitive technique for corneal nerve activity. The training objectives of this project are designed to develop the career of a budding physician-scientist interested in the topic of neural regeneration in ophthalmology. This fellowship project will be guided by expert mentorship of a team that includes a leading corneal physician-scientist and electrophysiologists from both UIC and Weill Cornell.