Identifying niche factors regulating distinct properties of AT2 stem cells

项目总结 一些严重的呼吸系统疾病会导致气体交换问题，而气体交换是 肺部。其中一些是突然发生的，比如严重肺炎造成的肺损伤，而另一些则会发展成 如慢性阻塞性肺病和特发性肺纤维化(IPF)。有一些证据表明， 慢性呼吸衰竭的部分原因是肺失去维持自身的能力。 由于正常发挥这一作用的常驻肺干细胞功能障碍。因此，发现 肺干细胞在整个生命过程中被调控的特定分子和细胞机制可能是 有助于了解COPD和IPF的发病机制。实现对肺的这种深刻的理解 干细胞调控可能会改进预测、诊断甚至药物治疗的策略。 这样的疾病。此外，考虑到通过医用支气管镜可以很容易地接触到肺部，这是一种理想的方法 器官的靶向是输送健康的干细胞，这种干细胞可能会阻止疾病的进展，甚至产生 如果能成功地将它们移植到患病的肺中，情况就会有所改善。我们发现其中一个 气体交换区的功能细胞，肺泡II型(AT2)细胞，作为小鼠肺的干细胞 在整个生命周期内，并确定了几个调节其活动的因素。这项提议的目的是 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。我们会调查的 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到 产生新的细胞，它是如何获得对损伤做出短暂自我调节的能力的，以及 调节环境与干细胞本身一样重要，甚至比干细胞本身更重要。 寿命。我们的发现将大大加深我们对这些肺干细胞是如何 故意操纵以产生大量适合细胞移植的细胞，或通过药物 驱动它们的活动以达到治疗“再生长”的目的。

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.