Fatty acid binding-proteins and endocannabinoids in the retina; roles in glial reactivity and reprogramming of Muller glia into progenitor cells

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 阻断或刺激Müler神经胶质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，表明脂肪酸结合蛋白(FABP)和 内源性大麻素对Müler神经胶质细胞去分化和重编程为增殖性神经源性的影响 小鸡和小鼠的视网膜祖细胞。我们将研究Müler神经胶质细胞的表型和可塑性 在正常、受损和生长因子治疗的视网膜中，受FABP和内源性大麻素调节。我们会 使用药理学和遗传学方法的组合来选择性地激活或抑制FABP和 内源性大麻素信号。我们将比较和对比FABP和内源性大麻素信号如何影响 鸡和啮齿动物模型系统中具有不同固有特性的Müler神经胶质源性祖细胞的形成 视网膜再生的能力。我们预计，在完成本文件中描述的实验后 该提案将提供关于如何将成熟的Müler胶质细胞重新编程为 米勒神经胶质细胞来源的祖细胞再生视网膜神经元。识别和理解 为了开发新的治疗视力的方法，需要增强Müler神经胶质细胞的神经生成潜力的机制。 危害性疾病，如青光眼、视网膜色素变性和黄斑变性 视网膜神经元。

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 block 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 Fatty acid-binding proteins (FABPs) and endocannabinoids impact the de-differentation and reprogramming of Müller glia into proliferating, neurogenic retinal progenitors in chicks and mice. We will investigate how the phenotype and plasticity of the Müller glia are regulated by FABPs and endocannabinoids in normal, damaged and growth factor-treated retinas. We will use a combination of pharmacological and genetic approaches to selectively activate or inhibit FABPs and endocannabinoid-signaling. We will compare and contrast how FABPs and endocannabinoid-signaling impacts 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 mature Müller glia can be reprogrammed into Müller glia-derived progenitors that regenerate 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, retinitis pigmentosa and macular degeneration that involve the loss of retinal neurons.