Regulatory mechanisms of Na+ and fluid absorption across alveolar epithelium

肺中有效的气体交换需要肺泡空气空间几乎没有液体。已经确定，肺泡的液体清除主要由通过位于肺泡上皮细胞顶膜的ENaC通道的主动Na+转运驱动。ENaC的调节机制以及跨肺泡细胞的Na+和液体吸收是复杂的，并且仍然不完全清楚。自2005年以来，我们的研究计划旨在更好地了解控制肺泡Na+和液体吸收的机制。在过去的几年中，我们已经取得了一些重大进展，确定了几个关键的调控因素肺泡运输。事实上，我们已经确定了几个因素，包括另一类离子通道，K+通道，控制ENaC基因启动子活性和ENaC表达，以及肺泡Na+和液体运输的活动。 我们在未来5年的主要目标将是继续我们的研究计划，并进一步研究细胞和动物模型中肺泡Na+和液体转运的调节机制。我们的第一个研究轴将集中在控制ENaC表达和启动子活性的细胞内信号。特别是，将探讨细胞体积，膜电位和细胞内离子浓度的作用。在我们的第二个轴，我们将研究ENaC和K+通道调制液体运输通过肺泡单层在体外的生理影响，使用一种新的实验方法，在我们的实验室适应。我们还计划开发第三个研究方向，在动物模型中研究肺泡液体清除的调节机制。 我们的NSERC计划将提供更多的知识，在非病理条件下调节肺离子和液体运输的基本机制。此外，还将开发几种对科学界有用的新技术方法。最后，我们计划的多学科方面将对我们实验室的学生培训产生有益的影响。

Effective gas exchange in the lungs requires alveolar air spaces virtually free of liquid. It has been established that liquid clearance from alveoli is mainly driven by active Na+ transport through ENaC channels, located at the apical membrane of alveolar epithelial cells. The regulatory mechanisms of ENaC as well as Na+ and fluid absorption across alveolar cells are complex and remain incompletely understood. Since 2005, our research program thus aims at better understanding the mechanisms that control alveolar Na+ and liquid absorption. During the last few years, we have made some significant progress by identifying several crucial regulatory elements of alveolar transport. Indeed, we have identified several factors including the activity of another class of ion channels, the K+ channels, controlling ENaC gene promoter activity and ENaC expression, as well as alveolar Na+ and liquid transport. Our main goal over the next 5 years will be to pursue our research program and to further study the regulatory mechanisms of alveolar Na+ and fluid transport in cellular and animal models. Our first axis of research will focus on the intracellular signals controlling ENaC expression and promoter activity. In particular, the role of cell volume, membrane potential and intracellular ion concentrations will be explored. In our second axis, we will study the physiological impact of ENaC and K+ channel modulation on liquid transport through alveolar monolayers in vitro, using a new experimental approach adapted in our laboratory. We also plan to develop a third axis of research to examine the regulatory mechanisms of alveolar liquid clearance in an animal model. Our NSERC program will provide more knowledge of the fundamental mechanisms regulating lung ion and liquid transport in non-pathological conditions. In addition, several new technical approaches, useful for the scientific community, will be developed. Finally, the multidisciplinary aspect of our program will have a beneficial impact on the training of students in our laboratory.