Stimulation of Retinal Regeneration

刺激视网膜再生

• 批准号: 10386847
• 负责人: THOMAS A REH
• 金额: $ 37.71万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386847
• 关键词: ATAC-seq; Adult; Affect; Age related macular degeneration; Amacrine Cells; Amphibia; Area; Blindness; Brain; CRISPR/Cas technology; Cell Cycle; Cells; ChIP-seq; Complete Blindness; Degenerative Disorder; Development; Disease; Electrophysiology (science); Epigenetic Process; Face; Fishes; Gene Activation; Gene Expression; Genes; Genetic Transcription; Genomic approach; Glaucoma; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; In Vitro; Inherited; Injury; Ischemia; Knowledge; Lead; Lentivirus; Light; Mammals; Methods; MicroRNAs; Mitogens; Mitotic; Molecular; Muller' s cell; Mus; N-Methylaspartate; Natural regeneration; Nervous system structure; Neural Retina; Neurons; Patients; Persons; Photoreceptors; Production; Proliferating; Publications; Regenerative response; Retina; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Role; Scanning Electron Microscopy; Sensory; Slice; Source; Technology; Testing; Time; Tissue-Specific Gene Expression; Transgenic Mice; Vertebrates; Viral; Visual; Visual impairment; Zebrafish; advanced disease; chromatin remodeling; effective therapy; experimental study; ganglion cell; in vivo; insertion/deletion mutation; knockout gene; neuron regeneration; novel strategies; overexpression; patch clamp; photoreceptor degeneration; prevent; progenitor; programs; regeneration potential; regenerative therapy; response; retinal damage; retinal neuron; retinal progenitor cell; retinal regeneration; retinal stimulation; single-cell RNA sequencing; transcription factor; transdifferentiation; treatment strategy

Abstract ! Like other areas of the nervous system, the retina is subject to many acquired and inherited neuronal degenerative diseases. Since the retina provides the input for all visual sensory information to the brain, the loss of cells results in visual impairment and potentially complete blindness. Many retinal degenerative diseases affect only a subset of the retinal cells, although, frequently in more advanced disease, loss and reorganization of the entire retina can occur. In mammals, there is very limited regeneration of the degenerated cells; however, in fish, new neurons of all types regenerate from Müller glia (MG) following retinal damage and they are functionally integrated into the existing circuitry. Although mammals, including people, lack this ability, MG, the cellular source for regeneration, are present in all vertebrate retinas. We hypothesize that regeneration from mammalian MG is limited because they fail to express the proneural program of gene expression after injury. We have found that viral over-expression of a proneural transcription factor can partly reprogram mammalian MG to a neurogenic state in vitro. For in vivo confirmation, we generated a transgenic mouse to express Ascl1 in MG. When we induce Ascl1 expression in adult MG, the combination of Ascl1 and histone deacetylase (HDAC) inhibition can stimulate new neuron production from MG in adult mice after NMDA induced damage. The MG-derived neurons primarily resemble bipolar or amacrine cells, and form connections with the existing retinal circuitry. These results show for the first time that functional neurons can be regenerated in an adult mammalian retina and properly integrate within the existing host circuit, but raise a key question: Why do the MG only produce bipolar cells and amacrine cells? In this proposal we outline studies to better understand, and potentially overcome, the barriers to regeneration in mammalian retina. !

抽象的 呢 像神经系统的其他区域一样，视网膜受到许多获得和遗传的神经元的约束 退化性疾病。由于视网膜为大脑提供了所有视觉感官信息的输入，因此 细胞的丧失会导致视觉障碍和潜在的完全失明。许多永久退化 疾病仅影响残留细胞的一部分，尽管在更晚期疾病，丧失和 可以发生整个视网膜的重组。在哺乳动物中，再生的再生非常有限 退化的细胞；但是，在鱼类中，所有类型的新神经元从MüllerGlia（MG）再生 虽然哺乳动物，包括 所有脊椎动物视网膜中都存在人们，缺乏这种能力，Mg，是再生的细胞来源。我们 假设哺乳动物MG的再生是有限的，因为它们无法表达胸膜 受伤后基因表达的程序。我们发现，促肿瘤的病毒过表达 转录因子可以在体外部分重新编程哺乳动物MG到神经源。用于体内 确认，我们生成了一个转基因小鼠以在mg中表达ASCL1。当我们影响ASCL1时 在成年MG中的表达，ASCL1和Hisstone脱乙酰基酶（HDAC）抑制的组合可以刺激 NMDA诱导损伤后，来自成年小鼠的新神经元产生的新神经元产生。 MG衍生的神经元 首先类似于双极性或无聚氨酯细胞，并与现有的视网膜电路形成连接。这些 结果首次表明在成年哺乳动物视网膜中可以再生功能性神经元，并且 正确整合在现有主机电路中，但提出了一个关键问题：为什么MG仅生产 双极细胞和无链氨酸细胞？在此建议中，我们概述了研究以更好地理解，并有可能 克服了哺乳动物视网膜再生的障碍。 呢