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Modeling Rett syndrome with Patient-specific Induced Pluripotent Stem Cells.

机译:用患者特异性诱导多能干细胞模拟Rett综合征。

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摘要

Rett syndrome (RTT) is one of the leading causes of intellectual disability in girls. Mutations in the X-linked methyl-CpG-binding protein 2 ( MECP2) gene have been identified as the cause of RTT. Mouse and patient-derived induced pluripotent stem cell (iPSC) model systems have been developed to better understand the molecular roles of MeCP2/MECP2 and gain insight on the disease pathophysiology. Recently, there has been an interest in the determining the glial component of RTT pathology. To model the non-cell autonomous glial component in RTT pathology in a human-based system, we have developed a patient-derived RTT astrocyte/neuron co-culture system. We have validated a detrimental non-cell autonomous effect of RTT astrocytes, and by utilizing three different RTT mutational lines, have determined that this effect is consistent and is mediated in part by astrocyte secreted factors. We have also gone on to test the efficacy of neurotrophic factors in ameliorating this glial effect and have found insulin-like growth factor 1 (IGF-1) and its tripeptide cleavage product, Glycine-Proline-Glutamate (GPE), to increase the somal area and to promote neurite outgrowth in GABAergic interneurons.
机译:Rett综合征(RTT)是女孩智力残疾的主要原因之一。 X连锁的甲基CpG结合蛋白2(MECP2)基因中的突变已被确定为RTT的原因。已经开发了小鼠和患者衍生的诱导多能干细胞(iPSC)模型系统,以更好地了解MeCP2 / MECP2的分子作用,并深入了解疾病的病理生理学。最近,人们对确定RTT病理的神经胶质成分感兴趣。为了在基于人的系统中对RTT病理学中的非细胞自主神经胶质成分进行建模,我们开发了一种患者衍生的RTT星形胶质细胞/神经元共培养系统。我们已经验证了RTT星形胶质细胞的有害非细胞自主作用,并通过利用三种不同的RTT突变系,确定了这种作用是一致的,并部分地由星形胶质细胞分泌因子介导。我们还测试了神经营养因子改善神经胶质作用的功效,并发现了胰岛素样生长因子1(IGF-1)及其三肽裂解产物甘氨酸-脯氨酸-谷氨酸盐(GPE)来增加体液并促进GABA能神经元的神经突生长。

著录项

  • 作者单位

    The University of Wisconsin - Madison.;

  • 授予单位 The University of Wisconsin - Madison.;
  • 学科 Biology General.;Biology Cell.;Biology Genetics.;Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 177 p.
  • 总页数 177
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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