Regulatory mechanisms of Na+ and fluid absorption across alveolar epithelium

肺泡上皮钠和液体吸收的调节机制

• 批准号: 312177-2011
• 负责人: Brochiero, Emmanuelle
• 金额: $ 2.19万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=571703
• 关键词: Regulatory; mechanisms; Na+; fluid; absorption

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.

肺部有效的气体交换需要几乎没有液体的肺泡空间。已经确定，来自肺泡的液体清除率主要由位于肺泡上皮细胞的顶膜的ENAC通道的主动Na+转运驱动。 ENAC以及Na+的调节机制以及跨肺泡细胞的流体吸收是复杂的，并且仍然不完全理解。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，我们通过识别肺泡转运的几个关键调节元素取得了重大进展。实际上，我们已经确定了几个因素，包括另一类离子通道的活性，K+通道，控制ENAC基因启动子活性和ENAC表达以及肺泡Na+和液体传输。 在接下来的五年中，我们的主要目标是追求我们的研究计划，并进一步研究肺泡Na+和液体传输的调节机制。我们的第一个研究轴将集中于控制ENAC表达和启动子活性的细胞内信号。特别是，将探索细胞体积，膜电位和细胞内离子浓度的作用。在我们的第二个轴中，我们将使用在我们的实验室中改编的新实验方法研究ENAC和K+通道调节对通过牙槽单层通过肺泡单层传输的生理影响。我们还计划开发第三个研究轴，以检查动物模型中肺泡液体清除的调节机制。 我们的NSERC计划将提供更多有关在非病理条件下调节肺离子和液体运输的基本机制的知识。此外，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。