Novel growth factors and regenerative RGC subtypes for optic nerve regeneration

用于视神经再生的新型生长因子和再生 RGC 亚型

• 批准号: 10666784
• 负责人: Yuqin Yin
• 金额: $ 26.55万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666784
• 关键词: Adult; Apoptotic; Axon; Blindness; Brain; Cell Culture System; Cell Death; Cell Survival; Cells; Combined Modality Therapy; Cytoprotection; Data; Data Set; Dose; Eye; Genetic study; Goals; Growth; Growth Factor; Image; In Vitro; Inflammation; Inflammatory; Injury; Label; Ligands; Mammals; Mediating; Mediator; Methods; Modeling; Mus; Natural regeneration; Nerve Crush; Neurons; Optic Nerve; Optic Nerve Injuries; Peptide Receptor; Peptides; Recovery; Recovery of Function; Retinal Ganglion Cells; Systems Analysis; Testing; Time; Toxic effect; Trophic Factor Receptor; Vision; Visual; Work; antagonist; axon growth; axon regeneration; chemokine; chemokine receptor; combinatorial; effective therapy; experience; improved; in vivo; in vivo Model; in vivo evaluation; injured; nerve damage; neuroprotection; new growth; novel; optic nerve regeneration; receptor; regeneration model; regenerative; regenerative cell; resilience; response; retinal ganglion cell regeneration; screening; transcriptome; transcriptome sequencing; visual information

Project Abstract or Summary Following injury to the optic nerve in mammals, retinal ganglion cells (RGCs) cannot regenerate their axons and soon undergo apoptotic cell death, leading to permanent vision loss. Some degree of optic nerve regeneration can be induced experimentally but the extent of regeneration achieved to date remains away from the level of visual functional recovery required, pointing to the need for more effective therapies. Aside from testing well established growth factors and chance discoveries of several novel factors, a more systematic screening of as yet untested ligands to the many trophic factor and chemokine receptors that are expressed in adult RGCs could augment regeneration well beyond currently achievable levels. In recent genetic studies (RNA-Seq, FACS- purified cells), we have obtained an extensive list of growth factor, chemokine and peptide receptors that are expressed in adult RGCs, many of whose ligands have not been tested for effects on axon regeneration and RGC protection. To carry out the screening, we will use an adult RGC culture system and in vivo optic nerve regeneration models that have been used on our lab for 2 decades, and which have enabled us identify three previously unknown potent factors for optic nerve regeneration. The proposed studies will screen the ligands to the multiple receptors that are expressed in adult RGCs to discover novel factors for optic nerve regeneration and RGC survival. With significantly improved automated cell culture system, Aim 1 will carry out an in vitro bioactivity screen and verify hits in vivo, respectively. Aim 2 will screen which subtypes of RGCs are responding to the known effective treatments and the new hits from Aim 1. This will enable us develop combinatorial treatments to stimulate axon regeneration from multiple RGC subtypes simultaneously. Through these studies, we expect to promote considerably greater levels of axon growth than can be attained currently and ultimately bring us closer to improving visual function after optic nerve damage.

项目摘要或摘要 在哺乳动物的视神经受伤后，视网膜神经节细胞（RGC）无法再生其轴突，并且 很快会发生凋亡细胞死亡，导致永久视力丧失。一定程度的视神经再生 可以通过实验诱导，但是迄今为止达到的再生程度仍然远离 需要视觉功能恢复，指出需要更有效的疗法。除了测试很好 建立的增长因素和几个新因素的机会发现，更系统地筛选AS 然而未经测试的配体对成人RGC表达的许多营养因子和趋化因子受体可能 增强再生远远超出了目前可达到的水平。在最近的遗传研究中（RNA-Seq，FACS- 纯化的细胞），我们获得了广泛的生长因子，趋化因子和肽受体的清单 在成年RGC中表达，许多配体尚未对轴突再生的影响进行测试 RGC保护。为了进行筛查，我们将使用成人RGC培养系统和体内视神经 在我们的实验室使用了20年的再生模型，这使我们能够识别三个 以前未知的视神经再生的有效因素。拟议的研究将把配体筛选到 在成年RGC中表达的多种受体，以发现视神经再生的新因素 和RGC生存。随着自动细胞培养系统的显着改善，AIM 1将进行体外 生物活性筛选和分别在体内验证命中。 AIM 2将筛选哪些RGC的子类型正在响应 对AIM 1的已知有效疗法和新打击。这将使我们能够发展组合 同时从多个RGC亚型刺激轴突再生的处理。通过这些研究， 我们期望比目前获得的轴突增长水平要高得多 在视神经损伤后，使我们更接近改善视觉功能。