Muller glia: roles in retinal homeostasis and neuronal regeneration

描述（由申请人提供）：有越来越多的证据表明Muller胶质细胞是介导神经再生的视网膜祖细胞的来源。许多研究表明，Muller胶质细胞可以成为不同脊椎动物视网膜中的增殖祖细胞。几乎所有的报道都研究了急性损伤视网膜中的Muller胶质源性祖细胞。然而，很少有人知道的机制，刺激神经发生从穆勒胶质源性祖细胞在未受损的视网膜或视网膜经历缓慢，进行性变性。此外，与冷血脊椎动物相比，温血脊椎动物中视网膜神经元的再生是有限的。因此，鉴定允许和/或刺激来自Muller胶质源性祖细胞的神经再生的分泌因子和信号传导途径对于开发治疗人视网膜退行性疾病的新疗法至关重要。我们已经获得了初步的数据表明，通过糖皮质激素受体（GCR），p38 MAPK和来自其他类型的视网膜神经胶质细胞的信号显着影响米勒神经胶质细胞的神经发生潜力的信号。我们将研究不同类型的视网膜神经胶质细胞的协调活动， Muller胶质细胞、小胶质细胞和最近描述的非星形胶质细胞视网膜内胶质样（NIRG）细胞。我们已经确定了NIRG细胞作为一种不同类型的神经胶质细胞，存在于鸟类，犬科动物和灵长类动物的视网膜。我们认为NIRG细胞影响Muller胶质细胞的能力， 成为视网膜祖细胞。我们期望完成本提案中描述的实验将提供关于不同信号通路、分泌因子以及小胶质细胞和NIRG细胞如何影响Muller胶质细胞衍生的视网膜祖细胞形成的重要新信息。识别和理解增强Muller神经胶质细胞的神经原性潜力的机制是开发威胁视力的疾病的新疗法所必需的，例如涉及视网膜神经元丧失的青光眼和黄斑变性。 公共卫生相关性：彻底了解调节神经胶质细胞功能的机制对于开发治疗威胁视力的视网膜疾病的新疗法至关重要。视网膜Muller神经胶质细胞具有成为神经源性祖细胞的潜能。识别和理解调节Muller胶质源性祖细胞的神经发生潜力的机制是开发视网膜神经元替代疗法的关键。该提案旨在确定重要的胶质细胞相互作用和信号通路，增强Muller胶质细胞成为增殖祖细胞和产生新的功能神经元的能力。这个项目的目标是研究确定的分子机制和信号通路，调节神经胶质细胞的功能，与反应，增殖和神经元再生。所提出的研究结果将提供有价值的新的见解的因素和信号机制，调节胶质细胞间的通信和胶质细胞介导的神经元再生。

DESCRIPTION (provided by applicant): There is a rapidly growing body of evidence that Muller glia are a source of retinal progenitors to mediate neural regeneration. Many studies have demonstrated that Muller glia can become proliferating progenitor cells in the retinas of different vertebrate species. Nearly all reports have studied Muller glia-derived progenitors in acutely damaged retinas. However, little is known about the mechanisms that stimulate neurogenesis from Muller 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 Muller glia-derived progenitors is crucially important to developing new therapies to treat degenerative diseases of the human retina. We have obtained preliminary data indicating that signaling through the glucocorticoid receptor (GCR), p38 MAPK and signals derived from other types of retinal glia significantly impact the neurogenic potential of Muller glia. We will investigate the coordinated activity of different types of retinal glia including the Muller glia, microglia and the recently described Non-astrocytic Inner Retinal Glia-like (NIRG) cells. We have identified the NIRG cells as a distinct type of glial cell that is present in retina of birds, canines and primates. We believe that the NIRG cells influence the ability of Muller glia to become retinal progenitors. We expect that the completion of the experiments described in this proposal will provide significant new information regarding different signaling pathways, secreted factors, and how the microglia and NIRG cells influence the formation of Muller glia-derived retinal progenitors. Identification and understanding of the mechanisms that enhance the neurogenic potential of Muller glia is required to develop new therapies for sight-threatening diseases, such as glaucoma and macular degeneration that involve the loss of retinal neurons. PUBLIC HEALTH RELEVANCE: A thorough understanding of the mechanisms that regulate the functions of glial cells is crucially important to the development of new therapies to treat sight-threatening diseases of the retina. Retinal Muller glia is known to have the potential to become neurogenic progenitor cells. Identification and understanding the mechanisms that regulate the neurogenic potential of Muller glia-derived progenitors is key to developing neuron-replacement therapies for the retina. This proposal seeks to identify important glial interactions and signaling pathways that enhance the ability of Muller glia to become proliferating progenitors and produce new functional neurons. A goal of this project is to study defined molecular mechanisms and signaling pathways that regulate glial functions related to reactivity, proliferation, and neuronal regeneration. The findings produced by the proposed studies will provide valuable new insights into the factors and signaling mechanisms that regulate inter-glial communication and glia- mediated neuronal regeneration.