Muller glia: roles in retinal homeostasis and neuronal regeneration

描述(申请人提供)：有快速增长的证据表明穆勒神经胶质细胞是视网膜前体细胞的来源，以调节神经再生。许多研究表明，在不同脊椎动物的视网膜中，Muller胶质细胞可以成为增殖祖细胞。几乎所有的报告都研究了穆勒神经胶质来源的前体细胞在急性损伤的视网膜中的作用。然而，鲜为人知的是，在未受损的视网膜或正在经历缓慢、进行性退化的视网膜中，刺激Muller神经胶质衍生前体细胞神经发生的机制很少。此外，与冷血脊椎动物相比，温血脊椎动物视网膜神经元的再生是有限的。因此，识别允许和/或刺激Muller神经胶质前体细胞神经再生的分泌因子和信号通路对于开发治疗人类视网膜退行性疾病的新疗法至关重要。我们已经获得的初步数据表明，通过糖皮质激素受体(GCR)、p38MAPK和来自其他类型视网膜胶质细胞的信号显著影响Muller胶质细胞的神经发生潜能。我们将研究不同类型的视网膜神经胶质细胞的协调活动，包括 Muller胶质细胞、小胶质细胞和最近描述的非星形细胞视网膜内胶质样细胞(NIRG)。我们已经确认NIRG细胞是一种独特的神经胶质细胞，存在于鸟类、犬类和灵长类动物的视网膜中。我们认为NIRG细胞影响Muller神经胶质细胞 成为视网膜祖细胞。我们期望这项建议中描述的实验的完成将为不同的信号通路、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前体细胞的形成提供重要的新信息。为了开发新的视力威胁疾病的治疗方法，如青光眼和黄斑变性，涉及视网膜神经元丧失的青光眼和黄斑变性，需要识别和了解增强Muller胶质细胞神经生成潜力的机制。 公共卫生相关性：对神经胶质细胞功能调节机制的透彻理解对于开发治疗威胁视力的视网膜疾病的新疗法至关重要。已知视网膜Muller神经胶质细胞具有成为神经源性前体细胞的潜力。识别和了解调节Muller神经胶质前体细胞神经生成潜能的机制是开发视网膜神经元替代疗法的关键。这一建议旨在确定重要的神经胶质细胞相互作用和信号通路，以增强穆勒神经胶质细胞成为增殖前体细胞并产生新的功能神经元的能力。该项目的一个目标是研究明确的分子机制和信号通路，这些分子机制和信号通路调节与反应性、增殖和神经元再生相关的胶质功能。这些拟议研究的结果将为调节胶质细胞间通讯和胶质细胞介导的神经元再生的因素和信号机制提供有价值的新见解。

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.