Muller glia and neuronal regeneration in the retina

米勒神经胶质细胞和视网膜神经元再生

• 批准号: 7409563
• 负责人: ANDY J FISCHER
• 金额: $ 28.45万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-05 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409563
• 关键词: Acute; Cell Cycle; Cells; Chickens; Ciliary Neurotrophic Factor; Cues; Data; Development; Embryo; Environment; FGF1 gene; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Glial Fibrillary Acidic Protein; Gliosis; Immediate-Early Genes; Insulin; Insulin-Like Growth Factor II; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Mediating; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Natural regeneration; Nerve Regeneration; Neuroglia; Neuronal Differentiation; Neurons; Notch Signaling Pathway; Numbers; Pathogenesis; Pathway interactions; Phenotype; Process; Proliferating; Reaction; Research Personnel; Retina; Retinal Diseases; Signal Pathway; Signal Transduction; Somatomedins; Source; Stem cells; Testing; Transcription Coactivator; Transcriptional Activation; Transplantation; Up-Regulation; Vision; Work; base; cell type; inhibitor/antagonist; insight; notch protein; postnatal; precursor cell; prevent; progenitor; programs; protein expression; research study; response; retinal damage; retinal progenitor cell; transcription factor

DESCRIPTION (provided by applicant): The possibility of neural regeneration from glial cells has recently gained credibility and popularity. We have previously shown that large numbers of Muller glia in the postnatal chicken retina can re-enter the cell cycle, de-differentiate, express transcription factors normally expressed by retinal progenitors, and produce a few new neurons (Fischer and Reh, 2001 a). We found that Muller glia can become retinal progenitor-like cells in response to acute damage (Fischer and Reh, 2001 a) or in response to the combination of insulin and FGF2 (fibroblast growth factor 2) in the absence of damage (Fischer et al., 2002b). Thus, Muller glia hold the potential to act as a cellular source of neural regeneration within the retina. However, the mechanisms that regulate the ability of Muller glia to re-enter the cell cycle, become progenitor cells, and differentiate as neurons remain unknown and unexplored. The specific hypothesis that underlies this proposal is that MAP kinase, Jak/STAT and Notch signaling pathways regulate the different responses of Muller glia to retinal damage. Based on preliminary data we will test the following hypotheses. (1) MAP kinase pathways promote glial de-differentiation and proliferation, and suppress aspects of reactive gliosis such as GFAP (glial fibrillary acidic protein) expression. (2) CNTF (ciliary neurotrophic factor)/Jak-STAT signaling promotes glial maturation, promotes GFAP expression, and suppresses glial proliferation. (3) Notch-mediated signaling prevents neuronal differentiation from Muller glia-derived progenitors in acutely damaged retinas. (4) Mature, damaged retinas lack the cues required for neuronal differentiation of progenitor cells. This proposal provides specific aims and describes experiments to test the above-listed hypotheses. Data produced by these experiments will provide valuable information regarding the possibility that Muller glia can be used as a source of neural regeneration within the retina. In addition, the data will provide new insights into the secreted factors and signaling pathways that control gliosis and the ability of glial cells to re-enter the cell cycle. This information could be applied to not only stimulate neural regeneration to treat sight-threatening diseases of the retina, but also to control gliosis that may be detrimental to the pathogenesis of retinal disorders.

描述（由申请人提供）：神经胶质细胞的神经再生的可能性最近获得了信誉和流行。我们先前已经表明，产后视网膜中的大量穆勒神经胶质可以重新进入细胞周期，脱离分化，表达转录因子通常由视网膜祖细胞表达，并产生一些新的神经元（Fischer和Reh，Reh，2001 A）。我们发现，由于没有损伤，穆勒神经胶质可响应急性损伤（Fischer and Reh，2001 A）或胰岛素和FGF2（成纤维细胞生长因子2）的响应（Fischer等人，Fischer等人，2002b）而响应于胰岛素和FGF2（成纤维细胞生长因子2）的响应。因此，Muller Glia具有作为视网膜内神经再生的细胞来源的潜力。然而，调节穆勒胶质胶质重新进入细胞周期，成为祖细胞并随着神经元的分化的能力的机制仍然未知且未探索。该提案基础的具体假设是MAP激酶，JAK/STAT和Notch信号通路调节Muller Glia对视网膜损伤的不同反应。根据初步数据，我们将测试以下假设。 （1）MAP激酶途径促进神经胶质脱位和增殖，并抑制反应性神经胶质病的各个方面，例如GFAP（神经胶质原纤维酸性蛋白）的表达。 （2）CNTF（纤毛神经营养因子）/JAK-STAT信号传导促进神经胶质成熟，促进GFAP表达并抑制神经胶质增殖。 （3）Notch介导的信号传导可防止急性损坏的视网膜中穆勒胶质衍生祖细胞的神经元分化。 （4）成熟的，受损的视网膜缺乏祖细胞神经元分化所需的线索。该建议提供了特定的目的，并描述了测试上述假设的实验。这些实验产生的数据将提供有关Muller Glia可以用作视网膜内神经再生来源的可能性的宝贵信息。此外，数据将提供有关控制神经胶质病的分泌因子和信号通路的新见解，以及神经胶质细胞重新进入细胞周期的能力。该信息不仅可以应用于刺激神经再生以治疗视网膜的视力疾病，还可以控制可能不利于视网膜疾病发病机理的神经胶质病。