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Assessing Axonal Fate, Myelination and Visual Function Recovery after New Gene Treatment

评估新基因治疗后轴突命运、髓鞘形成和视觉功能恢复

基本信息

批准号：
10220982
负责人：
KEVIN Kyung PARK
金额：
$ 18.61万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220982
关键词：
Adult Animal Model Animals Antihistamines Axon Behavioral Assay Blood - brain barrier anatomy Brain Caliber Cell Differentiation process Chronic Clinical Research Combined Modality Therapy Consensus Cre driver Crush Injury Cyclic AMP Disease Electron Microscopy Future Generations Genes Genetic Glaucoma Histology Injections Intervention MEKs Membrane Modeling Multiple Sclerosis Mus Natural regeneration Nerve Crush Neuraxis Neurons Non-Prescription Drugs Oligodendroglia Optic Nerve Optic Nerve Injuries Optics Oral PTEN gene Patients Peroxidases Phase Photosensitivity Process PubMed Recovery Recovery of Function Relapse Reporting Retina Retinal Ganglion Cells STAT3 gene Signal Transduction Suggestion Testing Time Trauma Viral Vision Zymosan ascorbate axon injury axon regeneration cell type functional restoration gene therapy improved injured mouse genetics myelination nerve damage oligodendrocyte precursor optic nerve disorder optic nerve regeneration preclinical study regenerative regenerative treatment remyelination response retinal axon small hairpin RNA visual information

项目摘要

Retinal ganglion cells (RGCs) are the only neuronal type that relays visual information from the retina to the brain. Like other central nervous system (CNS) axons, RGC axons generally do not regenerate following damage, presenting a major obstacle for treating patients with optic nerve trauma or glaucoma. Previously, using optic nerve crush model, we and others have shown that different genetic interventions induce RGC axon regeneration in adult mice. However, despite the considerable numbers of regenerated axons, recovery of visual function has been limited or non-existent. It is generally viewed that axon regeneration alone is not enough to restore meaningful recovery of visual functions after axonal injury. Evidence indicates that remyelination facilitating saltatory conduction is another key step toward attaining functional restoration. Previously, different groups have reported the extent to which regenerated RGC axons are myelinated in adult mice. However, the results have been variable, raising a possibility that remyelination of RGC axons occurs only under certain conditions. Overall, it is unclear whether there is an optimal intervention for inducing both axon regeneration and remyelination. In this proposal, we will test a hypothesis that manipulating certain genes and treatments will permit both axon regeneration and remyelination. In the first aim, we will determine whether regenerated RGC axons are myelinated in the mice receiving different regenerative treatments. In the second aim, we will determine the degree to myelination is attained with myelinating-promoting treatment. Results obtained from these studies will provide valuable information on developing future therapies to regenerate injured retinal axons after trauma or in diseases.

视网膜神经节细胞（Retinalganglioncells，RGC）是唯一能传递视觉信息的神经元从视网膜到大脑与其他中枢神经系统（CNS）轴突一样，RGC轴突通常损伤后不能再生，这是治疗视神经损伤患者的主要障碍。神经损伤或青光眼以前，使用视神经挤压模型，我们和其他人已经表明，不同的遗传干预诱导成年小鼠RGC轴突再生。但尽管再生轴突的数量可观，视觉功能的恢复受到限制，根本不存在一般认为，轴突再生本身不足以恢复轴索损伤后视觉功能有意义的恢复。有证据表明髓鞘再生促进跳跃传导是实现功能恢复的另一个关键步骤。以前，不同的研究小组已经报道了再生的RGC轴突在多大程度上被破坏。在成年小鼠中有髓鞘。然而，结果是可变的，提出了一种可能性， RGC轴突的髓鞘再生仅在某些条件下发生。总体而言，尚不清楚是否存在诱导轴突再生和髓鞘再生的最佳干预。在这我们将测试一个假设，即操纵某些基因和治疗方法将允许这两种情况发生。轴突再生和髓鞘再生。在第一个目标，我们将确定是否再生研资局在接受不同再生治疗的小鼠中轴突有髓鞘。第二个目标，我们将决定髓鞘形成的程度是通过髓鞘形成促进治疗实现的。结果从这些研究中获得的信息将为开发未来的治疗方法提供有价值的信息，在创伤或疾病后再生受损的视网膜轴突。