Muller glia: roles in retinal homeostasis and neuronal regeneration

项目总结：有越来越多的证据表明，穆勒神经胶质细胞可能是视网膜的来源 促进神经再生的祖细胞。许多研究表明，穆勒胶质细胞可以成为 不同脊椎动物视网膜中增殖的祖细胞。大多数报道都对穆勒进行了研究 严重损伤的视网膜中的神经胶质细胞来源的前体细胞。然而，人们对这种机制知之甚少。 刺激Müler神经胶质来源的前体细胞在未受损的视网膜或经历缓慢、 进行性退化。此外，温血脊椎动物视网膜神经元的再生是 与在冷血脊椎动物中看到的相比有限。因此，对分泌因子的鉴定 以及允许和/或刺激Müler神经胶质来源前体细胞神经再生的信号通路是 对于开发治疗人类视网膜退行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kappa光的细胞信号- 活化B细胞链增强子κB和Zust Homolog 2增强子活性的影响 Müler胶质细胞的去分化和重新编程为增殖的、神经源性的视网膜前体细胞。我们会 探讨正常小鼠Müler神经胶质细胞的表型和可塑性受核因子κB和EZH_2的调节。 受损的和经生长因子治疗的视网膜。我们将使用药理学和遗传学的组合 选择性激活或抑制Müler神经胶质细胞中的NF、κB和EZH2.我们将比较和对比如何 NFEZH2B信号和κ活性对鸡和啮齿类动物Müler神经胶质细胞来源祖细胞形成的影响 具有不同固有视网膜再生能力的模型系统。我们预期在落成后 本提案中描述的实验将提供有关NFκB和EZH2. 影响成熟Müler神经胶质细胞、Müler神经胶质细胞来源前体细胞的形成及视网膜再生 神经元。增强Müler神经发生潜能机制的识别和理解 需要胶质细胞来为青光眼和黄斑等威胁视力的疾病开发新的治疗方法。 包括视网膜神经元丢失的变性。

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.