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

项目摘要 众所周知，早产儿患成人肺结核的风险更高 比足月出生的人更容易患病。其中最突出的是， 病毒感染后的疾病。这种增加易感性的机制是很差的 明白迄今为止，大部分研究都集中在 对感染的反应。随着最近对祖细胞的表征， 对于流感病毒诱导的修复，我们假设， 前早产人群的成熟肺有助于增加的严重性 病毒性疾病在这个建议中，我们将确定新生儿的侮辱，如高氧， 通常用于维持早产儿的生命， 祖细胞，损害其在流感感染后的修复能力。我们将使用 新生儿高氧和成人流感感染的小鼠模型， 概括了在人体中观察到的许多变化。如果新生儿 损伤直接影响祖细胞（Aim 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，该建议从微环境的角度解决了祖细胞控制问题。 独特且具有临床意义的角度我们预计我们的发现将揭示 祖细胞和相应的微环境受到影响，它们如何受到影响， 以及哪些关键信号在调节这些变化。

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.