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Role of early life hyperoxia on mesenchymal stem cell fate: their impact on age related disease

Role of early life hyperoxia on mesenchymal stem cell fate: their impact on age related disease
生命早期高氧对间充质干细胞命运的作用:它们对年龄相关疾病的影响
批准号:
10312537
负责人:
Michael A O'Reilly
金额:
$23.1万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-09-01 至 2023-05-31

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中文摘要
翻译
项目总结 生命早期暴露在环境污染物或毒素中会随着年龄的增长而改变健康和体能。 早产儿就是一个很好的例子,因为他们的肺暴露得太快,而且经常暴露在过量的 出生时的氧气。这些个体将面临生长衰竭、肺功能下降、宿主受损的风险。 对呼吸道病毒感染的反应,以及随着年龄的增长心血管疾病的发展。我们建立了 一种独特的小鼠模型,在出生时暴露于高水平的氧气(高氧)会导致肺和心脏 晚年的疾病。利用这个模型,我们现在提供了新的证据,证明新生儿高氧血症也会损害生长。 通过抑制脂肪堆积。从这些小鼠分离的骨髓间充质干细胞(BMSCs)生长 速度更慢,氧化程度更高。他们还表现出积累脂肪和分化为 脂肪细胞,可能是因为它们表达了更高水平的5‘-AMP激活的蛋白激酶(AMPK),这是一种主要的 能量平衡调节剂,抑制脂肪酸合成和细胞增殖。自从被氧化后 干细胞随着年龄的增长而增加,我们将检验新生儿高氧加速氧化的假设 随着小鼠年龄的增长,间充质干细胞的数量增加,从而改变了它们分化和产生脂肪的能力。在……里面 目标1,我们将确定新生儿高氧血症如何永久性地重新编程氧化状态,从而 骨、脂肪和肺间充质干细胞的分化。由于转基因SftpcEC-SOD小鼠未见生长障碍 都暴露在高氧中,Aim 2将确定细胞外抗氧化剂超氧化物的过度表达 肺泡上皮2型细胞的歧化酶可恢复MSCs的氧化状态和成脂能力。我们 也将确定EC-SOD是否保留了支持AT2的相邻脂成纤维细胞的分化 细胞动态平衡。对领域的影响:了解新生儿高氧是如何破坏脂肪生成的 这很重要,因为它将增加我们对早产如何在以后的生活中改变健康的理解。
英文摘要
PROJECT SUMMARY Exposure to environmental pollutants or toxins early in life can alter health and fitness as people age. Preterm infants are a prime example because their lungs are exposed too soon and often to excess amounts of oxygen at birth. These individuals are then at risk for growth failure, reduced lung function, impaired host response to respiratory viral infections, and development of cardiovascular disease as they age. We established a unique mouse model wherein exposure to high levels of oxygen (hyperoxia) at birth causes lung and heart disease later in life. Using this model, we now provide new evidence that neonatal hyperoxia also impairs growth by inhibiting fat accumulation. Bone marrow mesenchymal stem cells (BMSCs) isolated from these mice grew slower and were more oxidized. They also displayed reduced capacity to accumulate lipid and differentiate into adipocytes, possibly because they expressed higher levels of 5’-AMP activated protein kinase (AMPK), a master regulator of energy homeostasis that inhibits fatty acid synthesis and cell proliferation. Since the oxidation of stem cells increases with age, we will test the hypothesis that neonatal hyperoxia accelerates the oxidation of mesenchymal stem cells as mice age, thereby altering their ability to differentiate and produce fat. In Aim 1, we will determine how neonatal hyperoxia permanently reprograms the oxidation state and thus differentiation of bone, fat, and lung MSCs. Since growth failure is not seen when transgenic SftpcEC-SOD mice are exposed to hyperoxia, Aim 2 will determine if over-expression of the anti-oxidant extracellular superoxide dismutase by alveolar epithelial type 2 cells restores the oxidation state and adipogenic potential of MSCs. We will also determine whether EC-SOD preserves the differentiation of adjacent lipofibroblasts that support AT2 cell homeostasis. Impact on the Field: Understanding how neonatal hyperoxia disrupts adipogenesis is important because it will increase our understanding of how preterm birth alters health later in life.
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Role of early life hyperoxia on mesenchymal stem cell fate: their impact on age related disease
  • 批准号:
    10475250
  • 项目类别:
  • 资助金额:
    $19.25万
  • 财政年份:
    2021
  • 负责人:
    Michael A O'Reilly
  • 依托单位:
Effect of Neonatal Hyperoxia on Alveolar Development and Infection
  • 批准号:
    9172674
  • 项目类别:
  • 资助金额:
    $11.51万
  • 财政年份:
    2008
  • 负责人:
    Michael A O'Reilly
  • 依托单位:
Effect of Neonatal Hyperoxia on Alveolar Development and Infection
  • 批准号:
    9000732
  • 项目类别:
  • 资助金额:
    $38.38万
  • 财政年份:
    2008
  • 负责人:
    Michael A O'Reilly
  • 依托单位:
Effect of Neonatal Hyperoxia on Alveolar Development and Infection
  • 批准号:
    10001048
  • 项目类别:
  • 资助金额:
    $53.66万
  • 财政年份:
    2008
  • 负责人:
    Michael A O'Reilly
  • 依托单位:
海外基金