Mechanosensor Function in the Control of Gas Exchange Surface Size and Composition

项目摘要/摘要 随着每次吸气、呼气和整个发育、成熟、老化和 发病机制上，肺处于不断的机械张力下。生物物理力是怎样的 对它的感知和回应仍然知之甚少。在承压天然气交换的区域 在这个力的前面，张力分布在巨大的肺泡面上。在这项研究中，我们将 探讨由肺泡上皮细胞感受到的机械张力， 触发分子反馈环路，驱动气体的产生和再生 交换应用表面积。 在这个反馈环路的中心是Piezo，一个大型的膜局部通道，是一个 典型的机械传感器。最先在神经元中发现和研究的Piezo基因也是 在肺中广泛表达。我们的初步数据显示，虽然Piezo基因在 肺间充质或内皮细胞不会导致明显的肺泡结构缺陷， 灭活肺上皮中的这些基因，特别是Piezo2，导致肺泡简化 在出生后早期的肺中。在成人肺中，Piezo2在肺泡上皮中的丢失导致 极大地增加了对肺泡损伤的易感性，导致纤维化。在这项研究中，我们将 研究发育中的机械感觉回路的性质(目标1)和损伤修复 (目标2)。这些发现将促进我们对机械传感器如何调整大小的了解 和肺泡表面的成分。

PROJECT SUMMARY/ABSTRACT With each inhalation, exhalation and across development, maturation, aging and pathogenesis, the lung is constantly under mechanical tension. How the biophysical force is sensed and responded to remains poorly understood. In the gas exchange region that bears the front of this force, tension is distributed across the vast alveolar surface. In this study, we will investigate the central premise that mechanical tension, sensed by alveolar epithelial cells, triggers a molecular feedback loop that drives the generation and regeneration of the gas exchange surface area. At the center of this feedback loop is Piezo, a large membrane localized channel that is a quintessential mechanosensor. First discovered and studied in neurons, Piezo genes are also widely expressed in the lung. Our preliminary data show that while loss of Piezo genes in the lung mesenchyme or the endothelium did not lead to discernable alveolar structural defects, inactivating these genes, especially Piezo2, in the lung epithelium led to alveolar simplification in the early postnatal lung. In the adult lung, Piezo2 loss in the alveolar epithelium led to drastically increased susceptibility to alveolar damage, leading to fibrosis. In this study, we will investigate the nature of this mechanosensory circuit in development (Aim 1) and injury repair (Aim 2). The findings will advance our knowledge on how mechanosensation could tune the size and composition of the alveolar surface.