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

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 阻断或刺激来自Müller胶质源性祖细胞的神经再生的信号通路是 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，脂肪酸结合蛋白（FABP）和 内源性大麻素影响Müller神经胶质细胞的去分化和重编程， 小鸡和老鼠的视网膜祖细胞。我们将研究Müller胶质细胞的表型和可塑性如何影响神经元的功能。 在正常、受损和生长因子治疗的视网膜中，FABPs和内源性大麻素调节。我们将 使用药理学和遗传学方法的组合来选择性地激活或抑制FABPs， 内源性大麻素信号传导。我们将比较和对比FABP和内源性大麻素信号传导如何影响 Müller胶质源性祖细胞在鸡和啮齿类动物模型系统中的形成， 视网膜再生的能力。我们希望完成本报告中描述的实验 该提案将提供关于成熟的Müller胶质细胞如何重新编程为 Müller胶质细胞衍生的祖细胞，可再生视网膜神经元。确定和了解 需要增强Müller神经胶质细胞神经原潜能的机制来开发新的视力治疗方法， 威胁性疾病，如青光眼、色素性视网膜炎和黄斑变性， 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.