Comparative transcriptomic and epigenomic analyses of Muller glia reprogramming

Muller 胶质细胞重编程的比较转录组和表观基因组分析

基本信息

批准号：
9551199
负责人：
John D Ash
金额：
$ 57.62万
依托单位：
UNIVERSITY OF NOTRE DAME
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：
2016-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9551199
关键词：
ATAC-seq Animal Model Bioinformatics Birds Blindness Candidate Disease Gene Cell Differentiation process Cells ChIP-seq Chromatin Chromatin Structure Competence DNA Data Development Exposure to Fishes Gene Expression Gene Expression Profiling Gene Structure Genes Genetic Transcription Growth Factor Human In Situ In Situ Hybridization Individual Injury Light Mammals Messenger RNA MicroRNAs Modeling Molecular Molecular Conformation Muller&apos s cell Mus N-Methylaspartate Natural regeneration Neurons Organism Pathway interactions Population Primates Proliferating Property Quantitative Reverse Transcriptase PCR Refractory Regulator Genes Rest Retina Retinal Rodent Sampling Signal Pathway Societies Stem cells Stimulus Testing Transcriptional Regulation Treatment Factor United States Validation Vision Visual Acuity Visual impairment Work Zebrafish blind comparative design disability epigenomics gain of function in vivo infancy loss of function neurogenesis novel therapeutics overexpression prevent progenitor regenerative response retinal damage retinal neuron retinal progenitor cell retinal regeneration transcription factor transcriptome transcriptome sequencing transcriptomics virtual

项目摘要

Project Summary: One potentially important approach to restore vision is the regeneration of lost retinal neurons from an endogenous population of retinal cells, the Müller glia. To explore the potential of ultimately stimulating the resident Müller glia in the damaged human retina, we will take a comparative approach using zebrafish (regeneration competent), chick (regeneration limited), and mouse (regeneration refractory). We will conduct a comprehensive and unbiased, comparative analysis of gene expression and chromatin conformation in isolated retinal progenitor cells and Müller glia in developing zebrafish, chick, and mouse retinas. We will also study changes Müller glia from all three model organisms as they are activated/reprogrammed in response to retinal injury (light damage, NMDA) or exposure to extrinsic factors that are capable of inducing their activation in the absence of retinal damage. Aims 1 and 2 will generate transcriptome and chromatin data of genes and chromatin structures that are associated with formation of Müller glia progenitor cells. In Aim 3, we will integrate this data using newly developed bioinformatic analysis to identify transcription factors and transcriptional networks that control neurogenic competence in Müller glia from each organism. In Aim 4, we will validate and test candidate genes in regulating the dedifferentiation of Müller glia in zebrafish, chick, and mice, using a combination of gain- and loss-of-function approaches. This work will begin to identify the transcription factors and miRNAs that regulate the extent of retinal regeneration in the three different model organisms. Understanding how to restore Müller glia to a youthful status will enable targeted regenerative retinal therapies.

项目摘要：恢复视力的一种潜在重要方法是失去永久神经元的再生来自残留细胞的内源性群体Müller神经胶质。探索潜力最终，刺激居民在人类视网膜损害中的穆勒神经胶质使用斑马鱼（再生能力），雏鸡（再生有限）的比较方法，和鼠标（再生难治性）。我们将进行全面而公正的偏见，分离的视网膜中基因表达和染色质构象的比较分析祖细胞和müller神经胶质在发展斑马鱼，雏鸡和小鼠视网膜中。我们也会研究在激活/重新编程的情况下从所有三种模型生物中都改变了MüllerGlia 响应视网膜损伤（轻损伤，NMDA）或暴露于外部因素目标1和2将产生基因和染色质结构的转录组和染色质数据与 Müller神经胶质祖细胞的形成。在AIM 3中，我们将使用新的开发了生物信息学分析以识别转录因子和转录网络该控制每个生物体的Müller神经胶质中的神经源能力。在AIM 4中，我们将验证和测试候选基因在确定斑马鱼，小鸡和小鼠，使用功能丧失方法的结合。这项工作将开始确定调节视网膜再生程度的转录因子和miRNA 三种不同的模型生物。了解如何将MüllerGlia恢复到年轻状态将使有针对性的再生残留疗法。