Mechanisms underlying Muller glia’s regenerative potential

穆勒胶质细胞再生潜力的机制

• 批准号: 10458085
• 负责人: DANIEL J GOLDMAN
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458085
• 关键词: Adopted; Adult; Biological Assay; Blinded; Blindness; Brain; Cell Transplantation; Cell division; Cells; Characteristics; Development; Disease; Disease Progression; Event; Exhibits; Eye diseases; Fishes; Gene Expression; Gene Expression Profile; Genes; Genetic; Glaucoma; Goals; Grant; Heterogeneity; Individual; Injury; Lateral; Lead; Macular degeneration; Mammals; Morphology; Muller' s cell; Multipotent Stem Cells; Mus; Natural regeneration; Nerve Degeneration; Neuroglia; Neurons; Persons; Play; Population; Proliferating; Property; Radial; Regenerative response; Research; Resistance; Retina; Retinal Degeneration; Retinitis Pigmentosa; Role; Scientist; Signal Pathway; Signal Transduction; Site; Specific qualifier value; Structure; System; Testing; Vision; Zebrafish; adult stem cell; base; disability; injured; insight; neuron regeneration; notch protein; postnatal; programs; regeneration potential; regenerative; repaired; response; response to injury; restoration; retinal neuron; retinal progenitor cell; retinal regeneration; stem cell population; stem cells; stemness; transcriptome; transcriptome sequencing; transcriptomics

Summary Blinding eye diseases, like glaucoma, macular degeneration, and retinitis pigmentosa cause neuronal degeneration and lead to severe disability. The restoration of lost neurons using cell transplantation holds promise, but the degenerating retina may prove resistant to exogenous cell integration as it undergoes structural remodeling with disease progression. An alternative approach is to use endogenous stem cells for retinal neuron regeneration. Remarkably, in zebrafish, Müller glia can function as stem cells and regenerate retinal neurons lost to injury or disease. Although Müller glia are found in both the zebrafish and mammalian retina, and share structure and function; only in fish do they regenerate new neurons. Over the past decade, we have learned a lot about the genetic programs and signaling pathways that regulate Müller glia reprogramming and proliferation in zebrafish; however, we still lack an understanding of why they can mount a regenerative response in fish, but not in mammals. It seems likely this information resides in Müller glia’s quiescent state. Interestingly, Notch signaling has recently emerged as an important difference between pro- regenerative Müller glia in the zebrafish retina and non-regenerative Müller glia in the mammalian retina. In zebrafish Müller glia, Notch signaling is active in the basal state and must be suppressed for regeneration to ensue; however, in mice Notch signaling is essentially absent from Müller glia beyond postnatal stages. Interestingly, Notch signaling is also associated with radial glial stem cells in the brain and its suppression is necessary for their cell division and neuronal regeneration. Furthermore, Notch signaling can amplify stochastic events by lateral inhibition and thereby, may drive Müller cell heterogeneity. Zebrafish Müller glia heterogeneity is suggested by differences in gene expression, spontaneous proliferation, and response to retinal injury. In this grant we propose to further characterize Müller glia cell heterogeneity in the uninjured zebrafish retina and connect this heterogeneity to Müller glia’s regenerative potential. In addition, we will investigate how Notch signaling impacts the Müller glia transcriptome to regulate its regenerative properties. It is anticipated that these studies will provide new insights into retina regeneration in zebrafish and lead to new strategies for stimulating Müller glia’s regenerative response in mammals.

概括 盲目的眼部疾病，例如青光眼，黄斑变性和色素性视网膜炎引起神经元 变性并导致严重的残疾。使用细胞移植者恢复丢失的神经元 承诺，但是退化的视网膜可能证明对外源细胞的整合具有抗性 结构重塑，疾病进展。另一种方法是将内源干细胞用于 视网膜神经元再生。值得注意的是，在斑马鱼中，müller神经胶质可以充当干细胞并再生 视网膜神经元因受伤或疾病而失去。虽然在斑马鱼和哺乳动物中都发现了穆勒神经胶质 视网膜，共享结构和功能；只有在鱼类中，它们才能再生新的神经元。在过去的十年中， 我们对调节MüllerGlia的遗传程序和信号通路有了很多了解 斑马鱼的重编程和增殖；但是，我们仍然对他们为什么可以安装一个 鱼类的再生反应，而不是哺乳动物。似乎这个信息位于MüllerGlia的 静态。有趣的是，Notch信号最近已成为主要差异 斑马鱼视网膜中的再生müller神经胶质和哺乳动物视网膜中的非再生müller神经胶质。 斑马鱼müllerglia，Notch信号在基本状态下活跃，必须抑制以再生至 随后；但是，在产后阶段以外的Müller神经胶质基本上不存在小鼠凹口信号。 有趣的是，Notch信号传导也与大脑中的径向神经胶质干细胞有关，其抑制是 其细胞分裂和神经元再生所必需的。此外，Notch信令可以放大 通过横向抑制，随机事件可能会驱动müller细胞异质性。斑马鱼müller神经胶质 基因表达，赞助增殖以及对 视网膜损伤。在这笔赠款中，我们建议进一步表征未受伤的Müller神经胶质细胞异质性 斑马鱼视网膜，并将这种异质性与穆勒·格利亚（MüllerGlia）的再生潜力联系起来。此外，我们将 研究Notch信号如何影响müller胶质转录组以调节其再生特性。 预计这些研究将为斑马鱼的视网膜再生提供新的见解，并导致新的见解 刺激MüllerGlia在哺乳动物中的再生反应的策略。