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.

摘要 我们建议促进受损视神经或视束的长距离轴突再生， 成年哺乳动物的视觉功能，通过增强成熟的内在生长能力和生长锥动力学 神经元我们将研究抑制let-7和/或上调其抑制因子lin 28和lin 41在视网膜病变中的作用。 细胞促进视神经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 还将研究是否上调细胞骨架TACC 3蛋白刺激戏剧性轴突再生， 直接瞄准生长锥随着年龄的增长，CNS神经元失去了再生轴突的能力，这限制了 损伤后功能恢复。许多基因已被确定为控制成熟的生长能力 神经元，但没有一个被转化为临床应用。最好的目标可能是那些有潜力 同时影响多个基因。其中let-7 miRNA似乎对调节年龄很重要， 轴突再生的依赖性下降。我们建议通过以下方法来增强成熟神经元的生长能力： 靶向lin 28/let-7/lin 41途径。因为轴突切断的CNS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 TACC 3基因。我们假设let-7通路调节了神经元轴突的再生， 靶向这一途径加上细胞骨架TACC 3基因刺激了强大的轴突再生和功能 恢复视觉通路。使用PI实验室开发的新型AAV载体，我们将确定 抑制let-7和/或上调视网膜细胞中的lin 28、lin 41或TACC 3是否促进强健的轴突 再生和功能恢复的成年啮齿动物与视神经或道损伤。目标1：研究 无论是let-7抑制剂、LIN 28或LIN 41的单独或组合病毒载体的玻璃体内注射 增强成年小鼠的视神经轴突再生、视网膜神经节细胞存活和功能恢复。在Aim中 2，我们将使用我们的AAV载体来研究上调TACC 3是否刺激戏剧性的轴突再生 以及靶向let-7和TACC 3信号的联合疗法是否产生更好的轴突再生， 功能恢复与视神经轴突损伤的成年啮齿动物比任何一个单独的方法。利用我们独特 病毒载体不仅有可能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，而且还开发实用和有效的策略，以促进轴突再生， 哺乳动物的功能恢复。我们的实验采用联合策略，靶向体细胞神经元和 程序和生长锥细胞骨架动力学应刺激进一步轴突再生和功能 复苏因此，我们预计在成年哺乳动物中确定非常有前途的再生策略。我们 在损伤后给药的病毒载体可应用于多个轴突束， 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， 这将使许多患者的生命得到改善，并减轻患者，家庭和公众的经济负担。