Regeneration of rod photoreceptors from Muller glial cells in adult mouse retina

成年小鼠视网膜穆勒胶质细胞的视杆细胞再生

基本信息

批准号：
9099335
负责人：
Bo Chen
金额：
$ 39.8万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9099335
关键词：
Adult Adverse effects Age related macular degeneration Amacrine Cells Blindness Cell Cycle Cell Cycle Progression Cells Cessation of life Dependovirus Development Disease Event Gene Transfer Goals Homeostasis Injury Lead Mammals Mediating Methods Molecular Mus National Eye Institute Natural regeneration Neuroglia Neurons Neurotoxins Pathway interactions Pattern Phosphorylation Photoreceptors Play Property Regulation Research Retina Retinal Retinal Degeneration Retinal Ganglion Cells Retinitis Pigmentosa Role Signal Pathway Signal Transduction Source Staging Stem cells Supporting Cell Testing Vision Visual impairment Zebrafish beta catenin cell type cold blooded vertebrate in vivo in vivo regeneration killings meetings mouse model nerve stem cell neurotoxic photoreceptor degeneration progenitor public health relevance regenerative repaired response retinal neuron retinal progenitor cell retinal rods success transcription factor vision science

项目摘要

DESCRIPTION (provided by applicant): Müller glial cells (MGs) are the primary support cells in the vertebrate retina. In cold-blooded vertebrates such as zebrafish, MGs are a source of stem cells for they can readily re-enter the cell cycle and replenish lost neurons, establishing a powerful self-repair mechanism. In mammals, however, MGs are naturally quiescent and lack regenerative capability. Photoreceptors are the most abundant cells in the mammalian retina and they mediate the first step in vision. The death of photoreceptors is a leading cause of vision impairment and blindness in major retinal degenerative diseases including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Extensive research efforts aimed at restoring the regenerative capability of MGs in mammals have met with little success. Current strategies for MG-derived photoreceptor regeneration rely on retinal injury and treatment of the whole retina with various factors. Retinal injury kills retinal neurons in the first place. Global treatment of the entire retina may lead to undesirable side effects in untargeted cells. The long-term goal of our research is to understand the molecular and cellular pathways underlying MG-derived photoreceptor regeneration, and to develop strategies to activate the regenerative capability of mammalian MGs for retinal self-repair. We propose to reprogram adult mouse MGs, in vivo, for regeneration of rod photoreceptors without retinal injury, through the following Aims: Aim 1) Investigate whether Wnt signaling is an injury-induced signaling pathway to activate MG proliferation. We will examine whether neurotoxic injury activates Wnt signaling and further test whether inhibition of Wnt signaling suppressed injury-induced MG proliferation. To target MGs cell-type-specifically, we will develop a gene transfer method targeting MGs cell-type-specifically. Aim 2) Restore the retinal progenitor/stem cell status of MGs through activation of Wnt signaling, without introduction of retinal injury. We will investigate whether gene transfer of β-catenin activates Wnt signaling and MG proliferation without retinal injury. GSk3β regulates Wnt signaling by phosphorylation of β-catenin leading to its degradation. We will examine whether deletion of GSK3β activates Wnt signaling and MG proliferation without retinal injury. Aim 3) Guide the differentiation of MG-derived retinal progenitor/stem cells to rod photoreceptors. We will guide the differentiation of MG-derived retinal progenitor/stem cells by gene transfer of transcription factors that are essential for rod photoreceptor cell fate determination and differentiation during retinal development, and test whether MG-derived new rods develop molecular, structural, and functional properties of native rods. Our proposed research will significantly advance our understanding of the basic mechanisms and functional implications of MG-derived rod photoreceptor regeneration in adult mammalian retina, and will set the stage for retinal self-repair in a major group of retinal degenerative diseases typically characterized by photoreceptor degeneration.

描述（由申请人提供）：穆勒胶质细胞（MG）是脊椎动物视网膜中的主要支持细胞，在斑马鱼等冷血脊椎动物中，MG 是干细胞的来源，因为它们可以很容易地重新进入细胞周期并发挥作用。补充丢失的神经元，建立强大的自我修复机制，然而，MG 是自然静止的并且缺乏再生能力。光感受器的死亡是哺乳动物视网膜中最丰富的细胞，它们介导视觉的第一步，是导致年龄相关性黄斑变性（AMD）和色素性视网膜炎（RP）等主要视网膜退行性疾病中视力障碍和失明的主要原因。旨在恢复哺乳动物 MG 再生能力的广泛研究工作收效甚微，目前 MG 衍生的光感受器再生策略依赖于视网膜损伤和整体治疗。视网膜损伤首先会杀死视网膜神经元，对整个视网膜进行全面治疗可能会导致非目标细胞产生不良副作用。衍生的光感受器再生，并制定激活哺乳动物 MG 再生能力以进行视网膜自我修复的策略。我们建议在体内重新编程成年小鼠 MG ，以实现视杆细胞的再生。目的：目的 1）研究 Wnt 信号是否是损伤诱导的信号通路，以激活 MG 增殖。我们将检查神经毒性损伤是否激活 Wnt 信号，并进一步测试 Wnt 信号是否抑制损伤诱导的信号通路。为了针对 MG 细胞类型特异性，我们将开发一种针对 MG 细胞类型特异性的基因转移方法。目标 2) 恢复视网膜。我们将研究 β-catenin 的基因转移是否会激活 Wnt 信号传导，以及 GSk3β 是否通过 β-catenin 磷酸化来调节 Wnt 信号传导而不会导致视网膜损伤。我们将检查 GSK3β 的缺失是否会激活 Wnt 信号传导和 MG 增殖而不损伤视网膜。目标 3) 指导 MG 衍生的分化。视网膜祖细胞/干细胞到视杆细胞我们将通过转录因子的基因转移来指导 MG 衍生的视网膜祖细胞/干细胞的分化，这些转录因子对于视网膜发育过程中视杆细胞感光细胞的命运决定和分化至关重要，并测试 MG 衍生的新视杆细胞是否发育分子、结构、我们提出的研究将显着促进我们对成年哺乳动物视网膜中 MG 衍生的视杆细胞再生的基本机制和功能意义的理解，并为视网膜奠定基础。主要特征为光感受器变性的视网膜退行性疾病的自我修复。