权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms underlying Muller glia’s regenerative potential

穆勒胶质细胞再生潜力的机制

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

总结