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首页> 外文学位 >Immune Dysfunction in the Ts65Dn mouse model of Down Syndrome: Potential Role(s) of Reactive Oxygen Species (ROS) and Alterations in IL-7Ralpha Expression.
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Immune Dysfunction in the Ts65Dn mouse model of Down Syndrome: Potential Role(s) of Reactive Oxygen Species (ROS) and Alterations in IL-7Ralpha Expression.

机译：唐氏综合症的Ts65Dn小鼠模型中的免疫功能障碍：活性氧（ROS）的潜在作用和IL-7Ralpha表达的改变。

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摘要

Down Syndrome (DS), a genetic disease caused by a triplication of chromosome 21, is characterized by increased markers of oxidative stress. In addition to cognitive defects, DS is characterized by hematologic disorders such as myelodysplastic syndrome, premature thymic involution and increased incidence of infections and leukemia. However, the potential causes of these defects have not been fully elucidated. The goal of this study was to examine hematopoietic stem cell, lymphoid progenitor cell, and mature lymphocyte function in DS using the Ts65Dn mouse model, which contains a segmental triplication of mouse chromosome 16 that is partially syntenic to human chromosome 21. Analysis of hematopoietic progenitor populations showed that Ts65Dn mice possessed fewer functional hematopoietic stem cells (HSC) and a significantly decreased percentage of bone marrow lymphoid progenitors. Increased reactive oxygen species (ROS) and markers of oxidative stress were detected in HSC populations and were associated with a loss of quiescence and increased apoptosis. Bone marrow progenitor, immature thymocyte, and mature lymphocyte populations expressed diminished levels of the IL-7Ralpha chain, which was associated with decreased proliferation and increased apoptosis. Modulating oxidative stress in vitro suggested that oxidative stress induced by diminished glutathione levels selectively leads to decreased IL-7Ralpha expression, and inhibits the survival of IL-7Ralpha-expressing hematopoietic progenitors, potentially linking increased ROS and immunopathology. Other possible mechanisms identified in Ts65Dn mice that could induce diminished IL-7Ralpha expression in DS are increased microRNA expression and inhibition of the Notch pathway. The data suggest that hematopoietic stem cell, lymphoid progenitor cell, and mature lymphocyte defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signaling may alter hematologic development in Ts65Dn mice. Therefore, the current study may support modulation of redox balance and IL-7Ralpha expression as possible therapeutic targets to treat immune dysfunction in DS and may provide a starting point for the manipulation of redox balance to modulate the immune response.
机译：唐氏综合症（DS）是一种由21号染色体三倍重复引起的遗传性疾病，其特征是氧化应激的标志物增加。除了认知缺陷外，DS的特征还在于血液系统疾病，例如骨髓增生异常综合症，过早的胸腺退化以及感染和白血病的发生率增加。但是，尚未完全阐明这些缺陷的潜在原因。这项研究的目的是使用Ts65Dn小鼠模型检查DS中的造血干细胞，淋巴样祖细胞和成熟淋巴细胞功能，该模型包含部分与人类21号染色体同义的小鼠16号染色体的三份重复。种群显示Ts65Dn小鼠拥有较少的功能性造血干细胞（HSC），并且骨髓淋巴祖细胞的百分比显着降低。在HSC人群中检测到增加的活性氧（ROS）和氧化应激的标志物，并与静止性丧失和凋亡增加有关。骨髓祖细胞，未成熟胸腺细胞和成熟淋巴细胞群体的IL-7Rα链水平降低，这与增殖减少和凋亡增加有关。体外调节氧化应激提示谷胱甘肽水平降低引起的氧化应激选择性导致IL-7Ralpha表达降低，并抑制表达IL-7Ralpha的造血祖细胞的存活，这可能与ROS和免疫病理学升高有关。在Ts65Dn小鼠中确定的其他可能诱导DS中IL-7Ralpha表达减少的可能机制是增加的microRNA表达和Notch途径的抑制。数据表明，造血干细胞，淋巴样祖细胞和成熟的淋巴细胞缺陷是DS免疫功能低下的原因，氧化应激增加和细胞因子信号传导减少可能会改变Ts65Dn小鼠的血液学发育。因此，当前的研究可能支持氧化还原平衡的调节和IL-7Ralpha表达作为治疗DS免疫功能障碍的可能治疗靶点，并可能为操纵氧化还原平衡调节免疫反应提供起点。

著录项

  • 作者

    Lorenzo, Laureanne Pilar E.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Health Sciences Human Development.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 188 p.
  • 总页数 188
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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