Cellular and molecular mechanisms of alveolar repair

项目摘要 急性呼吸窘迫综合征（ARDS）的死亡或慢性肺功能障碍是一个可怕的后果 肺泡气体交换区的急性损伤。除了治疗细菌性肺炎的抗生素， 在某些情况下，抗炎药物，如皮质类固醇，没有具体的治疗方法，除了 补充氧气和通气支持。因此，迫切需要更好地了解 牙槽骨损伤得到修复，如果修复不充分，则无法恢复的原因是什么 气体交换功能一旦精确的细胞和分子再生和适应不良的肺泡 反应被确定，我们可以继续合理地设计新颖和具体的治疗方法，以促进 修复.我们最近以高分辨率绘制了肺泡上皮细胞的肺泡再生反应， I型（AT 1）细胞消融，揭示了几个意想不到的机制。除了传统的AT2 干细胞增殖，我们确定了另外两种再生机制。第一个是即时的 AT2细胞的转分化而没有预先增殖，随后是常驻双核AT2的有丝分裂 在健康的肺中发现的祖细胞。我们还确定了反复AT 1细胞消融的病理反应， 包括AT2干细胞过度增殖，表面活性剂功能丧失和AT1细胞受损 分化在这里，我们计划充实这些再生程序的分子和细胞调节 并确定它们对通过防止毛细血管泄漏来维持适当气体交换的生理影响 和肺水肿。总之，我们将应用最先进的精确细胞类型消融和损伤 以高时间分辨率阐明肺泡上皮细胞和分子基础的实验方法 上皮修复

PROJECT SUMMARY Death or chronic lung dysfunction from acute respiratory distress syndrome (ARDS) is a dreaded consequence of acute injury to the alveolar gas exchange region of lung. Other than antibiotics for bacterial pneumonia and in some cases anti-inflammatory medications like corticosteroids, there are no specific therapies beyond supplementary oxygen and ventilatory support. Thus, there is an urgent need to better understand how acute alveolar injury is repaired and in cases when this is insufficient, what are the reasons for the failure to recover gas exchange function. Once the precise cellular and molecular regenerative and maladaptive alveolar responses are identified, we can move on to rationally engineer novel and specific treatments to promote repair. We have recently mapped at high resolution the alveolar regenerative response to alveolar epithelial type I (AT1) cell ablation, which revealed several unexpected mechanisms. In addition to conventional AT2 stem cell proliferation, we identified two other regenerative mechanisms. The first was immediate transdifferentiation of AT2 cells without prior proliferation, followed by mitosis of resident binucleated AT2 progenitors found in healthy lungs. We also identified pathological responses from repeated AT1 cell ablation consisting of excessive AT2 stem cell proliferation with loss of surfactant function and impaired AT1 cell differentiation. Here, we plan to flesh out the molecular and cellular regulation of these regenerative programs and to determine their physiological impact on maintaining proper gas exchange by preventing capillary leak and pulmonary edema. In summary, we will apply precise cell type ablation and injury with state-of-the-art experimental approaches to clarify at high temporal resolution the cellular and molecular basis of alveolar epithelial repair.