Muller glia: roles in retinal homeostasis and neuronal regeneration

项目摘要：有越来越多的证据表明，米勒胶质细胞可以是视网膜神经元的来源。 祖细胞促进神经再生。许多研究表明，Müller胶质细胞可以成为 在不同脊椎动物物种的视网膜中增殖祖细胞。大多数报告都研究了穆勒 急性损伤视网膜中的胶质源性祖细胞。然而，人们对这种机制知之甚少， 刺激未受损视网膜或经历缓慢， 进行性退化此外，温血脊椎动物视网膜神经元的再生是 与冷血脊椎动物相比是有限的。因此，分泌因子的鉴定 以及允许和/或刺激来自Müller胶质源性祖细胞的神经再生的信号传导途径， 这对于开发治疗人视网膜变性疾病的新疗法至关重要。我们有 获得了令人信服的新的初步数据，表明通过核因子κ-光- 活化B细胞链增强子（NFκB）和Zeste增强子同源物2（EZH 2）的活性影响 Müller胶质细胞的去分化和重编程为增殖的神经原性视网膜祖细胞。我们将 研究NFκB和EZH 2如何调节正常Müller胶质细胞的表型和可塑性， 受损和生长因子治疗的视网膜。我们将使用药理学和遗传学的结合 选择性激活或抑制Müller胶质细胞中NFκB和EZH 2的方法。我们将比较和对比 NFκ B信号和EZH 2活性影响鸡和啮齿动物Müller胶质源性祖细胞的形成 具有不同视网膜再生固有能力的模型系统。我们预计， 本提案中描述的实验将提供关于NFκB和EZH 2如何 影响成熟Müller胶质细胞、Müller胶质细胞源性祖细胞的形成和视网膜再生 神经元识别和理解增强Müller神经原性潜能的机制 神经胶质细胞是开发新的治疗视力威胁的疾病，如青光眼和黄斑 涉及视网膜神经元丧失的变性。

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.