Muller glia and neuronal regeneration in the retina

描述(由申请人提供)：神经胶质细胞再生的可能性最近获得了可信度和受欢迎。我们以前已经证明，出生后鸡视网膜中的大量Muller胶质细胞可以重新进入细胞周期，去分化，表达视网膜前体细胞正常表达的转录因子，并产生一些新的神经元(Fischer和Reh，2001a)。我们发现Muller胶质细胞可以在没有损伤的情况下对急性损伤(Fischer和Reh，2001a)或胰岛素和FGF2(成纤维细胞生长因子2)的组合做出反应，成为视网膜祖细胞样细胞(Fischer等，2002b)。因此，穆勒胶质细胞具有作为视网膜内神经再生的细胞来源的潜力。然而，调控Muller胶质细胞重新进入细胞周期、成为祖细胞和分化为神经元的机制仍然未知和未被探索。支持这一假设的具体假设是，MAP激酶、Jak/STAT和Notch信号通路调节Muller神经胶质细胞对视网膜损伤的不同反应。基于初步数据，我们将检验以下假设。(1)MAP激酶通路促进胶质细胞的去分化和增殖，抑制反应性胶质细胞增生症的某些方面，如GFAP(胶质纤维酸性蛋白)的表达。(2)CNTF(睫状神经营养因子)/JAK-STAT信号通路促进胶质细胞成熟，促进GFAP表达，抑制胶质细胞增殖。(3)在急性损伤的视网膜中，Notch介导的信号通路阻止了从Muller神经胶质细胞来源的前体细胞向神经元分化。(4)成熟、受损的视网膜缺乏祖细胞神经分化所需的信号。这份提案提供了具体的目标，并描述了检验上述假设的实验。这些实验产生的数据将提供有关穆勒胶质细胞可用作视网膜内神经再生来源的可能性的有价值的信息。此外，这些数据将为控制胶质细胞增生和胶质细胞重新进入细胞周期的能力的分泌因子和信号通路提供新的见解。这些信息不仅可以用来刺激神经再生来治疗危及视力的视网膜疾病，还可以用来控制可能对视网膜疾病的发病机制不利的胶质增生。

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.