Retinal Ganglion Cell Dendrite and Synapse Regeneration in Glaucoma: the Role of Insulin Signaling.

青光眼中的视网膜神经节细胞树突和突触再生：胰岛素信号传导的作用。

• 批准号: 10627930
• 负责人: Adriana Di Polo
• 金额: $ 60.94万
• 依托单位: UNIVERSITY OF MONTREAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627930
• 关键词: Address; Adenosine Monophosphate; Automobile Driving; Axotomy; Blindness; Brain; Cell Communication; Cell physiology; Cells; Cessation of life; Clinical Trials; Clinical Trials Design; Complex; Cytoskeleton; Data; Dendrite Regeneration; Dendrites; Disease; Electrophysiology (science); FRAP1 gene; Functional disorder; Glaucoma; Goals; Impairment; Injury; Insulin; Knowledge; Magnetism; Mediating; Mediator; Microspheres; Modeling; Monitor; Mus; Natural regeneration; Neuronal Dysfunction; Neurons; Ocular Hypertension; Onset of illness; Optic Nerve; Outcome; Pathologic; Pathology; Patients; Positioning Attribute; Process; Protein Kinase; Proteins; Recovery; Regenerative response; Regulation; Retina; Retinal Ganglion Cells; Risk Factors; Role; Safety; Symptoms; Synapses; Techniques; Testing; Therapeutic; Time; Traction; Translations; Vision; Work; axon regeneration; cell injury; clinical candidate; clinical development; efficacy validation; experimental study; functional restoration; gain of function; gene therapy; high intraocular pressure; in vivo imaging; innovation; insight; insulin signaling; knowledge translation; loss of function; neuron loss; nonhuman primate; novel; pre-clinical; pressure; regenerative; regenerative approach; repaired; restoration; retinal ganglion cell regeneration; retinal neuron; sensor; sight restoration; translational potential; visual information

Glaucoma is the leading cause of irreversible blindness worldwide. Loss of vision in glaucoma is caused by the selective death of retinal ganglion cells (RGCs). Rapid retraction of RGC dendrites with synapse disintegration, identified as an early pathological change after glaucomatous injury, leads to neuronal dysfunction and death. Many studies have focused on axonal regeneration, yet little is known about the ability of RGCs to regenerate dendrites. We recently demonstrated that insulin administered after substantial dendritic arbor shrinkage promoted robust RGC dendrite regeneration after optic nerve axotomy and in a mouse glaucoma model. However, several key questions remain unanswered: 1) does insulin regenerate synapses and restore neuronal function after glaucomatous damage? 2) Is impaired insulin signaling a trigger for dendritic pathology in glaucoma? 3) What are the mechanisms driving insulin-mediated dendrite regeneration? 4) What is the translational potential of insulin for RGC repair? In this application, we propose studies that will fill this knowledge gap and test the overarching hypothesis that insulin signaling is crucial for dendrite regeneration and functional restoration in glaucoma. We will use established models of glaucoma in mice and non-human primates as well as gain- and loss-of-function paradigms and innovative approaches in three independent, yet complementary, specific aims. In Aim 1, we will test the hypothesis that insulin regenerates dendrites and synapses leading to sustained restoration of neuronal function. These studies will also determine whether different RGC subtypes have the ability to mount a strong regenerative response and reestablish appropriate synaptic connectivity. Experiments outlined in Aim 2, will test the hypotheses that: i) impaired insulin signaling impinging on the mammalian target of rapamycin (mTOR) mediates early dendritic pathology and synapse elimination, and ii) insulin-mediated dendrite regeneration involves downstream bona fide effectors of protein translation and cytoskeletal regulation. In Aim 3, we will test the hypothesis that insulin treatment, including gene therapy, will effectively promote long-term RGC dendrite regeneration and restore visual function in non- human primate glaucoma. We will capitalize on our ability to use longitudinal in vivo imaging and electrophysiological techniques to monitor disease onset, progression, and recovery. The outcome of this application will have a major impact on our understanding of novel mechanisms and targets that promote RGC dendritic and synaptic regeneration as well as restoration of visual function. Importantly, this project will generate rigorous and compelling pre-clinical data that will serve as a knowledge-translation springboard towards the clinical development of insulin as a therapeutic strategy for glaucoma.

青光眼是全世界不可逆转失明的主要原因。青光眼导致视力丧失的原因是 视网膜神经节细胞（RGC）的选择性死亡。 RGC 树突快速回缩，突触崩解， 被确定为青光眼损伤后的早期病理变化，导致神经元功能障碍和死亡。 许多研究都集中在轴突再生上，但对 RGC 的再生能力知之甚少 树突。我们最近证明，在树突乔木大幅收缩后施用胰岛素 在视神经轴突切除术后和小鼠青光眼模型中促进强健的 RGC 树突再生。 然而，几个关键问题仍未得到解答：1）胰岛素是否可以再生突触并恢复 青光眼损伤后神经元功能如何？ 2) 胰岛素信号受损是否会引发树突状病理 青光眼？ 3）驱动胰岛素介导的树突再生的机制是什么？ 4）什么是 胰岛素对于 RGC 修复的转化潜力？在本申请中，我们提出了将填补这一空白的研究 知识差距并测试胰岛素信号对树突再生至关重要的总体假设 和青光眼的功能恢复。我们将使用已建立的小鼠和非人类青光眼模型 灵长类动物以及功能获得和丧失的范式和创新方法在三个独立的，但 互补的、具体的目标。在目标 1 中，我们将检验胰岛素再生树突和 突触导致神经元功能的持续恢复。这些研究还将确定是否 不同的 RGC 亚型有能力产生强烈的再生反应并重建适当的 突触连接。目标 2 中概述的实验将测试以下假设： i) 胰岛素信号传导受损 撞击哺乳动物雷帕霉素靶标（mTOR）介导早期树突病理和突触 消除，ii) 胰岛素介导的树突再生涉及蛋白质的下游真正效应子 翻译和细胞骨架调节。在目标 3 中，我们将检验胰岛素治疗的假设，包括 基因治疗，将有效促进长期 RGC 树突再生并恢复非 人类灵长类青光眼。我们将利用我们使用纵向体内成像的能力 监测疾病发生、进展和恢复的电生理技术。这件事的结果 应用将对我们对促进 RGC 的新机制和目标的理解产生重大影响 树突和突触再生以及视觉功能的恢复。重要的是，该项目将 生成严格且令人信服的临床前数据，作为知识转化的跳板 致力于胰岛素作为青光眼治疗策略的临床开发。

项目成果

Utility of Light-Adapted Full-Field Electroretinogram ON and OFF Responses for Detecting Glaucomatous Functional Damage.

• DOI: 10.1167/tvst.12.8.16
• 发表时间: 2023-08-01
• 期刊: TRANSLATIONAL VISION SCIENCE & TECHNOLOGY
• 影响因子: 3
• 作者: Dunn, Michaela;Cull, Grant;Reynaud, Juan;Jennings, Dawn;Holthausen, Trinity;Di Polo, Adriana;Fortune, Brad
• 通讯作者: Fortune, Brad

AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma.

• DOI: 10.1186/s13024-021-00466-z
• 发表时间: 2021-06-29
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Belforte N;Agostinone J;Alarcon-Martinez L;Villafranca-Baughman D;Dotigny F;Cueva Vargas JL;Di Polo A
• 通讯作者: Di Polo A

Optical Coherence Tomography and Optical Coherence Tomography Angiography: Essential Tools for Detecting Glaucoma and Disease Progression.

光学相干断层扫描和光学相干断层扫描血管造影：检测青光眼和疾病进展的基本工具。

• DOI: 10.3389/fopht.2023.1217125
• 发表时间: 2023
• 期刊: Frontiers in ophthalmology
• 作者: Shiga,Yukihiro;Nishida,Takashi;Jeoung,JinWook;DiPolo,Adriana;Fortune,Brad
• 通讯作者: Fortune,Brad