Synapse rescue and neuroprotection in the retina

视网膜突触救援和神经保护

• 批准号: 10608828
• 负责人: Daniel Kerschensteiner
• 金额: $ 38.95万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608828
• 关键词: Acceleration; Adult; Affect; Anatomy; Award; Behavioral Assay; Biochemistry; Biological Assay; Blindness; Cell Adhesion Molecules; Cell Death; Cessation of life; Code; Communication; Complex; Cone; Data; Development; Disease; Disease Progression; Electrophysiology (science); Genetic; Genome engineering; Grant; Human; Image; Knock-out; Knockout Mice; Life; Ligands; Maintenance; Mediating; Modeling; Molecular; Mus; Mutation; Natural History; Nerve Degeneration; Nervous System; Nervous System Physiology; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Operative Surgical Procedures; Organ Donor; Pathogenesis; Pathway interactions; Patients; Pattern; Photoreceptors; Preparation; Proteomics; Resolution; Retina; Rod; Shapes; Signal Transduction; Specific qualifier value; Synapses; System; Tertiary Protein Structure; Testing; Therapeutic; Time; Translations; Viral; Virus; Vision; Visual impairment; Wild Type Mouse; combinatorial; functional disability; functional restoration; gene therapy; horizontal cell; inherited retinal degeneration; neural circuit; neuroprotection; overexpression; photoreceptor degeneration; preservation; prevent; protein complex; retinal neuron; retinal rods; synaptic function; synaptogenesis; transcriptome; translation to humans

Project Summary Nervous system functions, including vision, arises from precise patterns of synaptic communication. In neurodegenerative diseases, synapse loss can long precede cell death and predict functional impairments. We recently discovered that the cell adhesion molecule (CAM) Netrin-G ligand 2 (NGL2) is required for the maintenance of rod photoreceptor synapses throughout life and that viral delivery of NGL2 can restore synapse numbers and induce the formation of extra synapses in adult wild-type and Ngl2 knockout mice, respectively. Based on these findings, we hypothesized (1) that viral delivery of NGL2 may be able to rescue synapses in inherited retinal degenerations (IRDs), a genetically heterogenous group of diseases in which photoreceptors lose synapses and die causing visual impairments, including blindness. We also hypothesized (2) that NGL2- mediated synapse rescue may be neuroprotective and slow photoreceptor death. Our preliminary data support these hypotheses, which we further test in this proposal. In Aim 1, we will examine whether synapse loss and photoreceptor degeneration progress differently IRD models on wild-type and Ngl2 KO backgrounds. We will determine to what extent and at which time viral delivery of NGL2 can rescue synapses, protect photoreceptors, and preserve vision. Finally, we will assess whether NGL2-gene therapy generalizes across IRD models that differ in pathogenesis and disease progression. CAMs nucleate large protein complexes that control synapse formation, maintenance, and function. The molecular composition and signaling mechanisms of these complexes is mostly unknown. In Aim 2, we will analyze the composition of NGL2 complexes at photoreceptor synapses and determine the contributions of NGL2’s interaction partners to synapse maintenance, rescue, and neuroprotection. Many therapeutic approaches to neurodegeneration that succeed in mice are lost in translation to humans. Differences in the anatomy, cellular composition, transcriptome, and function of neural circuits in mice vs. humans contribute to this translational challenge. We have developed an organotypic culture system of human retinas of patients undergoing enucleation surgery and organ donors. We have established an IRD model in this system. In Aim 3, we use these advances to test the ability of NGL2 and its interaction partners to rescue synapses and protect photoreceptors in the human retina. Together our studies will determine the potential of CAM-gene therapy for the treatment of neurodegenerative disease. Our mutation-agnostic approach could be widely applicable for genetically heterogenous IRDs and may be adaptable to neurodegenerative disease in other parts of the nervous system.

项目摘要 神经系统的功能，包括视觉，都是由精确的突触通讯模式产生的。在 在神经退行性疾病中，突触丧失可以早于细胞死亡并预测功能损伤。我们 最近发现，细胞粘附分子（CAM）Netrin-G配体2（NGL 2）是细胞粘附所必需的。 维持视杆细胞突触，病毒递送NGL 2可以恢复突触 数目，并分别诱导成年野生型和Ng 12敲除小鼠中额外突触的形成。 基于这些发现，我们假设（1）病毒递送NGL 2可能能够拯救突触， 遗传性视网膜变性（IRD），一组遗传异质性疾病，其中光感受器 失去神经键并导致视觉障碍，包括失明而死亡。我们还假设（2）NGL 2- 介导的突触拯救可以是神经保护性的和缓慢的光感受器死亡。我们的初步数据支持 这些假设，我们在本提案中进一步测试。在目标1中，我们将检查突触丢失和 在野生型和Ng 12 KO背景下，IRD模型的光感受器变性进展不同。我们将 确定NGL 2的病毒递送在多大程度上和何时可以拯救突触，保护光感受器， 保护视力最后，我们将评估NGL 2基因治疗是否在IRD模型中推广， 不同的发病机制和疾病进展。CAM使控制突触的大蛋白复合物成核 形成、维持和功能。这些复合物的分子组成和信号机制 大部分是未知的。在目标2中，我们将分析感光突触中NGL 2复合物的组成 并确定NGL 2的相互作用伙伴对突触维持，拯救和 神经保护许多在小鼠身上成功的神经变性治疗方法在翻译中丢失了 对人类在解剖学、细胞组成、转录组和神经回路功能方面的差异， 小鼠与人的比较有助于这种翻译挑战。我们开发了一种器官型培养系统， 接受眼球摘除手术的病人和器官捐献者的人类视网膜。我们建立了IRD模型 在这个系统中。在目标3中，我们使用这些进展来测试NGL 2及其相互作用伙伴拯救 突触和保护人类视网膜中的光感受器。我们的研究将共同决定 CAM-基因疗法用于治疗神经退行性疾病。我们的突变不可知论方法 广泛适用于遗传异质性IRD，并可能适用于神经退行性疾病， 神经系统的其他部分。