Muller glia: roles in retinal homeostasis and neuronal regeneration

Muller 胶质细胞：在视网膜稳态和神经元再生中的作用

基本信息

批准号：
10019557
负责人：
ANDY J FISCHER
金额：
$ 39万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10019557
关键词：
Acute B-Cell Activation Biological Models Blood Communication Complex Data Degenerative Disorder Development Disease Enhancers Genetic Glaucoma Goals Growth Factor Histone-Lysine N-Methyltransferase Homeostasis Homologous Gene Light MAP Kinase Gene Macular degeneration Mediating Molecular Muller&apos s cell Natural regeneration Nerve Regeneration Neuraxis Neuroglia Neuronal Differentiation Neurons Nuclear Pathway interactions Pharmacology Phenotype Polycomb Proliferating Reporting Retina Retinal Degeneration Retinal Diseases Rodent Model Role Signal Pathway Signal Transduction Source Vertebrates Vision cold blooded vertebrate experimental study gene repression genetic approach human disease in vivo insight mouse model neurodevelopment neurogenesis neuroinflammation neuron loss neuronal survival notch protein novel novel therapeutics progenitor regenerative repaired retinal damage retinal neuron retinal progenitor cell retinal regeneration stem cells

项目摘要

Project Summary: There is a rapidly growing body of evidence that Müller glia can are a source of retinal progenitors to promote neural regeneration. Many studies have demonstrated that Müller glia can become proliferating progenitor cells in the retinas of different vertebrate species. Most reports have studied Müller glia-derived progenitors in acutely damaged retinas. However, little is known about the mechanisms that stimulate neurogenesis from Müller glia-derived progenitors in undamaged retinas or retinas undergoing slow, progressive degeneration. Furthermore, the regeneration of retinal neurons in warm-blooded vertebrates is limited compared to that seen in cold-blooded vertebrates. Therefore, the identification of the secreted factors and signaling pathways that permit and/or stimulate neural regeneration from Müller glia-derived progenitors is crucially important to developing new therapies to treat degenerative diseases of the human retina. We have obtained compelling novel preliminary data indicating that cell-signaling through the nuclear factor kappa-light- chain-enhancer of activated B cells (NFκB) and the activity of Enhancer of Zeste Homolog 2 (EZH2) impacts the de-differentation and reprogramming of Müller glia into proliferating, neurogenic retinal progenitors. We will investigate how the phenotype and plasticity of the Müller glia are regulated by NFκB and EZH2 in normal, damaged and growth factor-treated retinas. We will use a combination of pharmacological and genetic approaches to selectively activate or inhibit NFκB and EZH2 in Müller glia. We will compare and contrast how NFκB-signaling and EZH2-acitvity impact the formation of Müller glia-derived progenitors in chick and rodent model systems with different inherent capacities for retinal regeneration. We expect that the completion of the experiments described in this proposal will provide significant new information regarding how NFκB and EZH2 influence mature Müller glia, the formation of Müller glia-derived progenitors and regeneration of retinal neurons. Identification and understanding of the mechanisms that enhance the neurogenic potential of Müller glia is required to develop new therapies for sight-threatening diseases, such as glaucoma and macular degeneration that involve the loss of retinal neurons.

项目摘要：有迅速增长的证据表明MüllerGlia可以成为视网膜的来源祖细胞促进神经变成。许多研究表明，MüllerGlia可以成为不同脊椎动物的视网膜中的祖细胞增殖。大多数报告都研究了穆勒急性损坏的视网膜中的胶质衍生祖细胞。但是，关于机制知之甚少刺激不龄视网膜或视网膜中的Müller神经胶质衍生祖细胞的神经发生，进行性变性。此外，残留脊椎动物中残留神经元的再生是与在冷血脊椎动物中看到的相比有限。因此，识别分泌因素允许和/或刺激Müller胶质衍生祖细胞的神经再生的信号通路是对于开发新疗法以治疗人类视网膜的退行性疾病至关重要。我们有获得了令人信服的新型初步数据，表明通过核因子kappa-light-imight-the-symignal- 活化B细胞（NFκB）的链增强剂和Zeste同源2（EZH2）的增强剂的活性 Müller神经胶质的脱不同和重编程为增生的神经源性视网膜祖细胞。我们将研究如何在正常情况下由NFκB和EZH2调节Müller神经胶质的表型和可塑性受损和生长的因子处理的视网膜。我们将结合药物和遗传在Müller神经胶质中选择性激活或抑制NFκB和EZH2的方法。我们将比较和对比 NFκB信号和EZH2-AITVITY影响了小鸡和啮齿动物中Müller胶质衍生的祖细胞的形成模型系统具有不同的视网膜再生能力。我们希望完成本提案中描述的实验将提供有关NFκB和EZH2的重要新信息影响成熟的müller神经胶质，穆勒胶质衍生的祖细胞的形成和视网膜的再生神经元。鉴定和理解增强Müller神经源潜力的机制需要神经胶质性开发新疗法以进行威胁视力疾病，例如青光眼和黄斑涉及永久神经元丧失的变性。