Correlations of structure and function in regenerating corneal nerves

角膜神经再生过程中结构与功能的相关性

• 批准号: 9760302
• 负责人: Evguenia Ivakhnitskaia
• 金额: $ 5万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760302
• 关键词: Acute; Adult; Affect; Aftercare; Anatomy; Animal Model; Benzalkonium Chloride; Chemical Burns; Chicago; Clinical; Cornea; Corneal Injury; Data; Defect; Detection; Drops; Electrophysiology (science); Ensure; Epithelial; Esthesia; Eye diseases; Family; Fellowship; Growth; Growth Factor; Hour; Illinois; Image; Immunohistochemistry; In Vitro; Infection; Injections; Injury; Ion Channel; Irritants; Knockout Mice; Laboratories; Lead; Mentorship; Metabolic Diseases; Methods; Modality; Molecular; Monitor; Morphology; Mus; Natural regeneration; Nerve; Nerve Regeneration; Neurons; Neurophysiology - biologic function; Nociceptors; Numbness; Operative Surgical Procedures; Ophthalmology; Outcome; Pain; Patients; Peripheral; Persistent pain; Physicians; Population; Property; Publishing; Records; Recovery; Recovery of Function; Research; Scientist; Sensory; Severities; Signal Transduction; Structure; Supplementation; Surface; TRPV1 gene; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Training; Trauma; Treatment Efficacy; Treatment outcome; Universities; Vascular Endothelial Growth Factor B; Vascular Endothelial Growth Factors; afferent nerve; base; blink reflexes; career; clinically relevant; corneal epithelium; density; desensitization; design; doctoral student; extracellular; eye dryness; functional outcomes; healing; improved; in vivo; in vivo imaging; interest; lacrimal; member; nerve injury; nerve supply; ocular surface; painful neuropathy; receptor; relating to nervous system; repaired; targeted treatment; therapeutic candidate; therapy design; vision science

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.

摘要/项目摘要 角膜神经形成体内最密集的感觉网络，并为角膜提供营养支持 上皮。三种类型的模式构成了整体角膜神经群并传达离散的 通过对角膜表面的各种刺激做出反应来产生感觉。角膜损伤很常见 可能是多种原因造成的结果，从手术干预到代谢紊乱。虽然 角膜神经在受伤后能够再生，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长期变化。三者的具体功能恢复 损伤后的神经亚型仍然很大程度上未知，因此限制了对患者治疗结果的预测 和有效疗法的设计。该提案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 通过结合体内细胞外电生理学来实现，这是一种记录细胞外电生理学的高度灵敏的技术 利用神经成像、免疫组织化学和分子技术观察单个神经元的电活动。 拟议的角膜神经损伤疗法已被证明可以促进更快、更广泛的生长 体外和体内的神经。然而，人们对这些治疗的功能性后果知之甚少。 神经元活动。神经损伤的有效治疗必须确保神经功能的全面再生， 保持适当的刺激物检测阈值，同时避免痛苦的失火。 VEGF，一种内源性 损伤后在角膜中表达的分子，是角膜损伤的候选治疗剂。虽然已经是 在角膜损伤后的动物模型中补充时显示出具有亲神经作用， VEGF 应用的结果尚未得到表征。该提案的第二个目标将使用 电生理学、免疫组织化学、成像和分子技术来研究结构 VEGF 治疗对角膜神经亚型恢复的功能影响。 总的来说，这项研究将阐明再生角膜神经亚型的功能，并将 第一个测试 VEGF 作为角膜神经修复潜在疗法的功能影响。 该项目将由芝加哥大学伊利诺伊大学芝加哥分校 (UIC) 的一名医学博士/博士生进行 公立研究型大学，拥有一流的眼科和视觉科学系。这将是 通过结合评估神经元再生的结构和功能后果，其独特之处在于 经典分子方法与角膜神经活动敏感技术。本次培训目标 项目旨在发展对神经主题感兴趣的崭露头角的医生科学家的职业生涯 眼科再生。该奖学金项目将由一个团队的专家指导进行指导，其中包括 来自伊利诺伊大学芝加哥分校 (UIC) 和威尔康奈尔大学 (Weill Cornell) 的领先角膜医师科学家和电生理学家。