Identifying niche factors regulating distinct properties of AT2 stem cells

项目摘要 许多严重的呼吸道疾病引起气体交换问题，而气体交换是呼吸系统的主要功能。 肺其中一些是突然发作的，如严重肺炎造成的肺损伤，而另一些则是发展中国家的疾病。 慢性阻塞性肺疾病（COPD）和特发性肺纤维化（IPF）。有一些证据表明 慢性形式的呼吸衰竭部分是由于肺丧失了维持自身的能力， 这是由于通常发挥这一作用的常驻肺干细胞的功能障碍。因此，发现 在整个生命过程中调节肺干细胞的特定分子和细胞机制可能 有助于了解COPD和IPF的发展过程。对肺有了更深层次的了解 干细胞调控可能会导致预测、诊断甚至是治疗的策略得到改进 这样的疾病。此外，考虑到通过医学支气管镜检查容易接近肺部， 通过输送健康的干细胞来靶向器官，这些干细胞可能会阻止疾病进展，甚至产生 如果它们能成功移植到患病的肺中，就能改善病情。我们发现， 在气体交换区域的功能细胞，肺泡II型（AT 2）细胞，作为小鼠肺的干细胞 并确定了几个调节其活性的因素。本提案的目标是 通过研究当地环境，扩大我们对这些干细胞是如何调节的理解， 提供控制其活性的信号，包括增殖和分化。我们将调查 干细胞行为的三个具体和不同的方面，包括它是如何被诱导增殖， 产生新的细胞，它如何获得对损伤做出反应的瞬时调节自身的能力，以及是否 调节环境与干细胞本身一样重要，甚至更重要，以维持肺超过 寿命我们的研究结果将大大加深我们对这些肺干细胞是如何被 故意操纵以产生大量适合于细胞移植的细胞，或通过细胞移植， 驱动它们的活性用于治疗性“再生长”目的。

PROJECT SUMMARY A number of serious respiratory diseases cause problems with gas exchange, which is the principal function of the lungs. Some of these are sudden in onset, like lung injury from a severe pneumonia, while others develop over long periods of time, like COPD and Idiopathic Pulmonary Fibrosis (IPF). There is some evidence that the chronic forms of respiratory failure result from loss of the capacity of the lungs to maintain themselves, in part due to dysfunction of resident lung stem cells that normally perform this role. Therefore, discovering the specific molecular and cellular mechanisms by which lung stem cells are regulated throughout life may be helpful for understanding how COPD and IPF develop. Achieving this deep level of understanding about lung stem cell regulation may lead to improved strategies to predict, diagnose, and even pharmacologically treat such diseases. Furthermore, given the easy accessibility of the lung via medical bronchoscopy, it is an ideal organ to target with the delivery of healthy stem cells that might prevent disease progression or even produce improvement if they can be successfully transplanted into diseased lungs. We have found that one of the functional cells in the gas exchange region, the alveolar type II (AT2) cell, acts as a stem cell for mouse lung throughout the lifespan, and identified several factors that regulate its activity. The AIMS of this proposal are to expand our understanding of how these stem cells are regulated by studying the local environment that provides the signals that control their activity, including proliferation and differentiation. We will investigate three specific and distinct aspects of the stem cell behavior, including how it is induced to proliferate to generate new cells, how it attains the capacity to transiently regulate itself in response to injury, and whether the regulatory environment is as or more important than the stem cell itself for maintaining the lungs over the lifespan. Our findings will significantly deepen our understanding of precisely how these lung stem cells can be deliberately manipulated to generate large numbers suitable for cell transplantation, or by pharmacologically driving their activity for therapeutic 're-growth' purposes.