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: 10686123
• 负责人: SHUXIN LI
• 金额: $ 37.87万
• 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/10686123
• 关键词: Adult; Age; Axon; Axotomy; Blindness; Cell Survival; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Cytoskeletal Proteins; Cytoskeleton; Development; Failure; Family; Financial Hardship; Functional Regeneration; Gene Expression; Genes; Goals; Growth; Growth Cones; Individual; Injury; Lateral Geniculate Body; 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; Probability; Proteins; Quality of life; Recovery; Recovery of Function; Retina; Rodent; Role; Signal Transduction; TACC3 gene; Testing; Translating; Viral Vector; Vision; Visual; Visual Pathways; Visual System; Visual impairment; adeno-associated viral vector; age related; axon growth; axon injury; axon regeneration; cell growth; central nervous system injury; effective therapy; experimental study; improved; inhibitor; injured; injury recovery; innovation; insight; intravitreal injection; neuronal cell body; neuronal growth; novel; programs; regenerative; regenerative approach; regenerative therapy; repaired; retinal ganglion cell regeneration; 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 我们建议促进受伤的视神经或区域的长距离轴突再生以及恢复 成人哺乳动物的视觉功能通过增强内在的生长能力和成熟的生长锥动力学 神经元。我们将研究是否抑制let-7和/或上调其补品lin28和lin41 细胞促进具有视轴突损伤的成年哺乳动物的稳健轴突再生和功能恢复。我们 还将研究上调细胞骨架TACC3蛋白是否通过 直接靶向生长锥。中枢神经系统神经元失去了随着年龄的增长而再生轴突的能力，这限制了 受伤后的功能恢复。已经确定了许多基因来控制成熟的生长能力 神经元，但没有人转化为临床用途。最好的目标可能是有潜力的目标 简单影响多个基因。其中，Let-7 miRNA对于调节年龄很重要 - 轴突再生的依赖下降。我们建议通过 针对LIN28/LET-7/LIN41途径。因为轴突中枢神经系统中的营养不良生长锥有助于 轴突再生失败，我们还建议通过上调来增强细胞骨架生长动力学 tacc3基因。我们假设Let-7途径调节哺乳动物的轴突再生，并且 靶向该途径加上细胞骨架Tacc3基因刺激稳健的轴突再生和功能 恢复视觉途径。使用Pi实验室中开发的小说AAV矢量，我们将确定 在残留细胞中抑制Let-7和/或上调LIN28，LIN41或TACC3都会促进稳健的轴突 患有视神经或道损伤的成年啮齿动物的再生和功能恢复。目标1的建议 玻璃体内注射是对let-7抑制剂，lin28或lin41的个体或组合病毒矢量的注射 增强成年小鼠的视神经轴突再生，视网膜神经节细胞的存活和功能恢复。目标 2，我们将使用我们的AAV矢量来研究上调TACC3是否刺激急剧的轴突再生 以及针对Let-7和TACC3信号的组合疗法是否会产生更好的轴突再生和 具有视轴突损伤的成年啮齿动物的功能恢复都比任何一种单独的方法。使用我们的独特 病毒载体的潜力不仅有潜力为分子控制的重要新见解提供 成熟的中枢神经系统神经元，同时也制定实用有效的策略来促进轴突再生和 哺乳动物的功能恢复。我们的实验具有靶向两个体细胞神经元的策略 程序和生长锥细胞骨架动力学应刺激进一步的轴突再生和功能 恢复。因此，我们预计会确定成人哺乳动物中极为有希望的再生策略。我们的 病毒载体是受伤后给予的，可以应用于多个轴突区域，并且很容易翻译 进入临床试验。该项目的成功可能会扭转视觉功能缺陷，提高质量 许多患者的生活，并减少对患者，家庭和公众的财务燃烧。