VRC: Develop regenerative therapies for neurological vision loss

VRC：开发神经性视力丧失的再生疗法

• 批准号: 10395744
• 负责人: SHUXIN LI
• 金额: $ 39.63万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395744
• 关键词: Address; Adult; Age; Axon; Blindness; Cell Survival; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Cytoskeletal Proteins; Development; Failure; Family; Financial Hardship; Gene Expression; Genes; Goals; Growth; Growth Cones; Individual; Injury; Lateral Geniculate Body; Lead; Lesion; Mammals; Measures; Mediating; MicroRNAs; Microtubules; Molecular; Molecular Target; Mus; Natural regeneration; Neurologic; Neurons; Optic Nerve; Optic Nerve Injuries; Optic tract structure; Optics; Pathway interactions; Patients; Plus End of the Microtubule; Polymerase; Polymers; Proteins; Quality of life; Recovery; Recovery of Function; Retina; Retinal Ganglion Cells; Rodent; Role; Signal Transduction; TACC3 gene; Testing; Translating; Viral Vector; Vision; Visual; Visual Pathways; Visual impairment; Visual system structure; adeno-associated viral vector; age related; axon growth; axon injury; axon regeneration; base; cell growth; central nervous system injury; effective therapy; experimental study; improved; inhibitor/antagonist; injured; injury recovery; innovation; insight; intravitreal injection; neuronal cell body; neuronal growth; novel; programs; regenerative; regenerative approach; regenerative therapy; repaired; success; superior colliculus Corpora quadrigemina; targeted treatment

Abstract We propose to promote long-distance axon regeneration of injured optic nerve or tract and recovery of visual function in adult mammals by enhancing intrinsic growth capacity and growth cone dynamics of mature neurons. We will study whether inhibiting let-7 and/or upregulating its suppressors lin28 and lin41 in retinal cells promotes robust axon regeneration and functional recovery in adult mammals with optic axon injury. We will also study whether upregulating cytoskeletal TACC3 protein stimulates dramatic axon regeneration by targeting growth cones directly. CNS neurons lose the ability to regenerate axons with age, and this limits functional recovery after injury. Many genes have been identified to control the growth ability of mature neurons, but none have been translated to clinical use. The best targets are probably those with the potential to impact multiple genes simultaneously. Among them, let-7 miRNA seems important for regulating age- dependent decline in axon regeneration. We propose to enhance the growth capacity of mature neurons by targeting the lin28/let-7/lin41 pathway. Because dystrophic growth cones in axotomized CNS contribute to axon regeneration failure, we also propose to enhance cytoskeletal growth dynamics by upregulating the TACC3 gene. We hypothesize that the let-7 pathway regulates axon regeneration in mammalians and that targeting this pathway plus the cytoskeletal TACC3 gene stimulates robust axon regeneration and functional recovery of visual pathways. Using the novel AAV vectors developed in the PI’s lab, we will determine whether inhibiting let-7 and/or upregulating lin28, lin41, or TACC3 in retinal cells promotes robust axon regeneration and functional recovery in adult rodents with optic nerve or tract injury. Aim 1 proposes to study whether intravitreal injections of the individual or combined viral vectors for let-7 inhibitor, lin28, or lin41 enhance optic axon regeneration, retinal ganglion cells survival, and functional recovery in adult mice. In Aim 2, we will use our AAV vectors to study whether upregulating TACC3 stimulates dramatic axon regeneration and whether combination therapies targeting both let-7 and TACC3 signals yield better axon regeneration and functional recovery in adult rodents with optic axon injury than either individual approach. Use of our unique viral vectors has the potential not only to provide important new insights into the molecular control of growth in mature CNS neurons, but also to develop practical and effective strategies to promote axon regeneration and functional recovery in mammals. Our experiments with combined strategies to target both somatic neuronal program and growth cone cytoskeletal dynamics should stimulate further axon regeneration and functional recovery. We thus anticipate identifying extremely promising regenerative strategies in adult mammals. Our viral vectors, which are administered post-injury, can be applied to multiple axon tracts and readily translated into clinical trials. The success of this project may reverse the visual functional deficits, improve the quality of life in many patients, and reduce the financial burdens to patients, families, and the public.

抽象的 我们建议促进受损视神经或视束的远距离轴突再生和视神经的恢复 通过增强成熟哺乳动物的内在生长能力和生长锥动力学来改善成年哺乳动物的视觉功能 神经元。我们将研究是否在视网膜中抑制let-7和/或上调其抑制因子lin28和lin41 细胞促进视轴突损伤的成年哺乳动物的强健轴突再生和功能恢复。我们 还将研究上调细胞骨架 TACC3 蛋白是否会通过以下方式刺激显着的轴突再生 直接针对生长锥。随着年龄的增长，中枢神经系统神经元失去轴突再生的能力，这限制了 受伤后的功能恢复。已鉴定出许多基因控制成熟植物的生长能力 神经元，但尚未转化为临床应用。最好的目标可能是那​​些有潜力的人 同时影响多个基因。其中，let-7 miRNA似乎对于调节年龄很重要—— 轴突再生的依赖性下降。我们建议通过以下方式增强成熟神经元的生长能力 靶向 lin28/let-7/lin41 通路。因为中枢神经系统轴突中营养不良的生长锥有助于 轴突再生失败，我们还建议通过上调细胞骨架生长动力学 TACC3 基因。我们假设 let-7 通路调节哺乳动物的轴突再生，并且 靶向该通路加上细胞骨架 TACC3 基因可刺激强健的轴突再生和功能 视觉通路的恢复。使用 PI 实验室开发的新型 AAV 载体，我们将确定 抑制视网膜细胞中的let-7和/或上调lin28、lin41或TACC3是否会促进轴突的强健 患有视神经或视束损伤的成年啮齿动物的再生和功能恢复。目标1建议学习 无论是玻璃体内注射let-7抑制剂、lin28还是lin41的单独病毒载体还是组合病毒载体 增强成年小鼠的视轴突再生、视网膜神经节细胞存活和功能恢复。瞄准 2，我们将使用我们的AAV载体来研究上调TACC3是否刺激显着的轴突再生 针对 let-7 和 TACC3 信号的联合疗法是否能产生更好的轴突再生以及 与任何一种方法相比，患有视轴突损伤的成年啮齿动物的功能恢复效果更好。利用我们独特的 病毒载体不仅有潜力为细胞生长的分子控制提供重要的新见解 成熟的中枢神经系统神经元，还开发实用有效的策略来促进轴突再生和 哺乳动物的功能恢复。我们的实验采用针对体细胞神经元的组合策略 程序和生长锥细胞骨架动力学应该刺激进一步的轴突再生和功能 恢复。因此，我们期望在成年哺乳动物中找到极其有前途的再生策略。我们的 损伤后施用的病毒载体可以应用于多个轴突束并易于翻译 进入临床试验。该项目的成功可能会扭转视觉功能缺陷，提高视觉质量 改善许多患者的生活，并减轻患者、家庭和公众的经济负担。