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

• 批准号: 9598755
• 负责人: Bo Chen
• 金额: $ 28.58万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/9598755
• 关键词: Regeneration; rod; photoreceptors; Muller; glial

 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）：Müller神经胶质细胞（MGS）是脊椎动物视网膜中的主要支撑细胞。 ，在哺乳动物中，有力的自我修复机制是自然的Qiescent和缺乏的，是哺乳动物视网膜中最丰富的细胞。包括与年龄相关的Macualar变性（AMD）S色素（RP）。在不靶向的细胞中，OS的长期目标是理解MG衍生的分子和地窖途径的长期效果。对于带有视网膜损伤的杆状感受器的体内，AIM 1）研究小麦信号是激活MG损伤的损伤诱导的方法。开发靶向MGS细胞类型的基因2）通过激活Wnt信号，恢复MGS的视网膜祖细胞状态，而无需引入视网膜损伤。 β-catenininininininininininininninninnin的磷酸磷酸化，导致其降解的磷酸化。 感光细胞。我们将通过转录因子的基因转移来指导MG衍生的祖细胞/干细胞，这是杆光感受器细胞在发育过程中的分化，并测试MG衍生的新杆分子结构和是否具有天然杆的功能。通过光感受器变性。