Impact of Early-in-life Disruption of Lung Development on Adult Lung Progenitor Function

项目总结 众所周知，早产儿患成人肺部疾病的风险更高。 比那些足月出生的人更容易患上疾病。其中突出的是日益严重的 病毒感染后的疾病。这种易感性增加的机制尚不清楚。 明白了。到目前为止，大部分研究都集中在损伤阶段。 对感染的反应。最近对中枢神经前体细胞的特征进行了分析 对于流感病毒诱导的修复，我们假设受损的祖细胞活性在 前早产儿的成熟肺导致肺炎的严重程度增加 病毒性疾病。在这项提案中，我们将确定新生儿侮辱，如高氧血症， 它通常用于维持早产儿的生命，对肺部造成持久的影响 祖细胞，损害了他们在流感感染后的修复能力。我们将使用 一种新生儿高氧和成人流感感染的小鼠模型 总结一下在人类身上观察到的许多变化。我们将解决如果新生儿 INSTUT直接影响祖细胞(目标1)，或通过 间充质细胞微环境(AIM 2)或免疫细胞微环境(AIM 3)。 因此，该建议解决了由微环境从 独特且具有临床意义的角度。我们预计，我们的发现将揭示出 祖细胞和相应的微环境受到影响，它们是如何受到影响的， 调解这些变化的关键信号是什么？

PROJECT SUMMARY Infants born preterm are known to have higher risks of developing adult lung diseases than those born full term. Prominent among these is an increased severity of illness following viral infection. The mechanism of this increased susceptibility is poorly understood. Much of the research to date has focused on the damage phase of the response to infection. With recent characterization of the progenitor cells that are central to influenza virus-induced repair, we hypothesize that compromised progenitor activity in the mature lungs of the former preterm population contribute to the increased severity of viral illness. In this proposal, we will determine how neonatal insults such as hyperoxia, which is routinely used to sustain life in preterm infants, leave a lasting impact on lung progenitors, compromising their ability to repair following influenza infection. We will use a mouse model of neonatal hyperoxia and adult influenza infection, which together recapitulate many of the changes as observed in human. We will address if the neonatal insult impacts the progenitor cells either directly (Aim 1), or indirectly through the mesenchymal cell microenvironment (Aim 2) or immune cell microenvironment (Aim 3). This proposal thereby addresses progenitor control by the microenvironment from a unique and clinically significant angle. We anticipate that our findings will reveal which progenitors and corresponding microenvironments are affected, how they are affected, and what are the key signals that mediate these changes.