New models, new approaches, new horizons in corneal nerve regeneration

角膜神经再生的新模型、新方法、新视野

基本信息

批准号：
10334864
负责人：
Vivian Lee
金额：
$ 51.17万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334864
关键词：
AVIL gene Address Afferent Neurons Agonist Architecture Axotomy Biological Markers Biology Cellular biology Chemicals Cochlea Complex Conflict (Psychology)Cornea Corneal Diseases Data Development Disease EphB2 Receptor Functional disorder Future Gene Expression Genetic Genetic Transcription Genomics Glaucoma Glutamate Receptor Goals Growth Factor Health Histology Homeostasis Immunohistochemistry Incidence Infection Injury Investigational Therapies Knockout Mice LDL-Receptor Related Protein 1 Maintenance Mechanics Mediating Metabolic Methods Modeling Molecular Monitor Morphology Mus N-Methyl-D-Aspartate Receptors NR1 gene Natural regeneration Nerve Nerve Fibers Nerve Regeneration Nervous system structure Neuronal Plasticity Neurons Operative Surgical Procedures Optic Nerve Outcome Pain Pathway interactions Peripheral Peripheral Nervous System Pharmacology Play Positioning Attribute Protein Tyrosine Kinase Proteins Publishing Retina Role Schwann Cells Signal Transduction Signaling Molecule Stimulus Structure Supporting Cell System Tamoxifen Temperature Testing Therapeutic Therapeutic Intervention Time Tissues Trauma Trigeminal System Trigeminal nerve structure Work afferent nerve antagonist base corneal epithelial wound healing density experimental study glutamatergic signaling in vivo in vivo imaging in vivo regeneration injured innovation insight intravital imaging mouse genetics mouse model nerve supply new therapeutic target novel novel strategies ocular surface peripheral nerve regeneration regenerative restoration sciatic nerve targeted treatment therapeutic target therapy development transcriptomics two photon microscopy wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT The cornea is the most highly innervated structure in the body, supplied by the ophthalmic branch of the trigeminal nerve. As part of the peripheral nervous system, corneal nerves respond to pain, temperature, mechanical and chemical stimuli. They also secrete various trophic and growth factors, which are essential to the health and function of the cornea. However, corneal nerves are highly susceptible to injury through various mechanisms that include trauma, infections, metabolic imbalances, and therapeutic interventions such as refractive surgeries. Once injured, they fail to reestablish their baseline density or morphology, contributing to corneal dysfunction. Currently, there are no targeted treatments specific for corneal nerve regeneration. The long-term goal of this proposal is to develop therapies for corneal nerve regeneration. The objective is to determine key molecular mechanisms involved in corneal nerve regeneration to help inform new experimental and therapeutic interventions. The central hypothesis is the N-Methyl-D-aspartate receptors (NMDAR), a type of glutamate receptor, help restore corneal nerve density and morphology, and therefore, corneal function. The rationale underlying this proposal is that NMDARs have been shown to enhance nerve regeneration in other analogous peripheral nervous systems. However, their role in corneal nerve regeneration remains unknown. Additional justification for investigating the role of NMDARs in corneal nerve regeneration is based on other published findings: 1) NMDARs are expressed throughout the nervous system, including the trigeminal nerves; 2) they have been shown to regulate neuronal maintenance and plasticity; 3) they regulate Schwann cell activity, which are supporting cells essential to nerve regeneration; and 4) NMDARs cooperate with other signaling molecules that have been shown to regulate corneal nerve regeneration such as LDL-receptor-related protein-1 and Ephrin type-B receptor 2. Therefore, we propose three aims to support our hypothesis. AIM 1 will determine the role of NMDAR in corneal nerve maintenance and regeneration by conditionally deleting NMDAR in sensory nerves and Schwann cells independently. AIM 2 will determine the effect of modulating NMDAR levels on corneal nerve regeneration. AIM 3 will determine key downstream effectors, including the EphB2-Sox2 axis, with spatial transcriptomics, correlated with protein levels and morphologic changes during corneal nerve regeneration. We will pursue these aims using innovative genetic mouse models, intravital imaging, and spatial genomics. The proposed aims are significant because they will define new molecular pathways that will inform the development of future therapies. The immediate expected outcome of this work is rigorous interrogation of key pathways in corneal nerve regeneration in vivo and contribution to our fundamental understanding of peripheral nerve regeneration. The results will have an important direct positive impact because they will interrogate new experimental approaches and inform the development of targeted therapies for corneal nerve regeneration.

项目概要/摘要角膜是体内神经支配程度最高的结构，由眼科的眼科分支提供能量。三叉神经。作为周围神经系统的一部分，角膜神经对疼痛、温度、机械和化学刺激。它们还分泌各种营养因子和生长因子，这些因子对于角膜的健康和功能。然而，角膜神经很容易受到各种损伤。机制包括创伤、感染、代谢失衡和治疗干预，例如屈光手术。一旦受伤，它们就无法重建基线密度或形态，从而导致角膜功能障碍。目前，尚无针对角膜神经再生的针对性治疗方法。这该提案的长期目标是开发角膜神经再生疗法。目标是确定参与角膜神经再生的关键分子机制，以帮助为新的实验提供信息和治疗干预。核心假设是 N-甲基-D-天冬氨酸受体 (NMDAR)，它是一种谷氨酸受体，有助于恢复角膜神经密度和形态，从而恢复角膜功能。这这一提议的基本原理是 NMDAR 已被证明可以增强其他神经再生类似的周围神经系统。然而，它们在角膜神经再生中的作用仍然未知。研究 NMDAR 在角膜神经再生中的作用的其他理由基于其他已发表的研究结果：1) NMDAR 在整个神经系统中表达，包括三叉神经； 2）它们已被证明可以调节神经元的维持和可塑性； 3）它们调节雪旺细胞活性，它们是神经再生所必需的支持细胞； 4) NMDAR 与其他信令配合已被证明可以调节角膜神经再生的分子，例如 LDL 受体相关蛋白 1 和 Ephrin B 型受体 2。因此，我们提出三个目标来支持我们的假设。 AIM 1 将确定通过条件性删除感觉神经中的NMDAR来研究NMDAR在角膜神经维持和再生中的作用神经和雪旺细胞独立。 AIM 2 将确定调节 NMDAR 水平对角膜的影响神经再生。 AIM 3 将确定关键的下游效应器，包括 EphB2-Sox2 轴，并具有空间转录组学，与角膜神经再生过程中的蛋白质水平和形态变化相关。我们将利用创新的遗传小鼠模型、活体成像和空间基因组学来实现这些目标。这提出的目标很重要，因为它们将定义新的分子途径，为发展提供信息未来的治疗方法。这项工作的直接预期成果是对关键途径进行严格审问体内角膜神经再生及其对我们对周围神经的基本理解的贡献再生。结果将产生重要的直接积极影响，因为他们将质疑新的实验方法并为角膜神经再生靶向疗法的开发提供信息。