Contribution of pulmonary ionocytes and neuroendocrine cells to ion transport-mediated airway surface liquid maintenance

项目摘要/摘要 调节跨上皮细胞的离子运输对呼吸道的健康和功能至关重要。主动型 被动离子和水的运动负责维持纤毛通过的纤毛周液体层 可以移动粘液，保护呼吸道免受颗粒、刺激物和病原体的侵袭。在明确的情况下 由特定离子通道突变(CFTR)和获得性离子通道功能障碍引起的疾病的证据 在疾病严重程度(慢性阻塞性肺病、哮喘)期间，单个细胞类型的贡献 肺上皮细胞对离子转运的维持还知之甚少。我们的实验证据 表明肺离子细胞和神经内分泌细胞在呼吸道中的频率变化 上皮细胞培养导致离子传输特性的显著差异。总之，这些细胞类型，沿着 以簇状细胞为主，约占人气管上皮细胞总数的0.8%。肺 摘要离子细胞是一种新发现的呼吸道细胞类型，具有多种离子通道的极高表达。 在呼吸道中具有重要功能。离子细胞与肺神经内分泌的戏剧性影响 细胞对人类呼吸道培养的离子转运特性的影响，尽管它们的频率很低，但导致了我们的 这些细胞类型高度参与调节和维持离子转运平衡的假说 能够影响其他类型细胞的离子转运功能 细胞间通信。通过利用新的小鼠模型和将创新技术应用于初级 小鼠和人的呼吸道上皮细胞，这项建议中概述的研究将定义 这些罕见的细胞类型对呼吸道上皮细胞的整体离子转运功能也将起到决定作用 在这些细胞中有CFTR的表达。因此，我们将充分描述肺离子细胞的重要性，并 神经内分泌细胞对离子转运介导的呼吸道表面液体调节及识别潜在细胞和 治疗常见呼吸道疾病的离子通道靶点。

PROJECT SUMMARY/ABSTRACT Regulation of ion transport across the epithelium is vital to the health and function of the airways. Active and passive ion and water movement is responsible for maintaining a periciliary fluid layer through which cilia can move mucus and protect the airways against particles, irritants, and pathogens. While there is clear evidence of disease caused by specific ion channel mutations (CFTR) as well acquired ion channel dysfunction during/contributing to disease severity (COPD, asthma), the contribution of individual cell types of the pulmonary epithelium to ion transport maintenance is poorly understood. Our experimental evidence demonstrates that alterations in the frequencies of pulmonary ionocytes and neuroendocrine cells in airway epithelial cultures result in dramatic differences in ion transport properties. Altogether, these cell types, along with tuft-like cells, comprise about 0.8% of the total cell numbers in the human tracheal epithelium. Pulmonary ionocytes are a newly identified cell type in the airways with extremely high expression of many ion channels with vital functions in the respiratory tract. The dramatic impact of ionocytes and pulmonary neuroendocrine cells on the ion transport properties of human airway cultures despite their rare frequencies led to our hypothesis that these cell types are highly involved in the regulation and maintenance of ion transport balance across the entire epithelium and are able to impact ion transport functions in other cell types through intercellular communication. By utilizing novel murine models and applying innovative techniques to primary murine and human airway epithelial cells, the research outlined in this proposal will define the contribution of these rare cell types to the overall ion transport functions of the airway epithelium and will also define the role of CFTR in these cells. We will thereby fully characterize the significance of pulmonary ionocytes and neuroendocrine cells to ion transport-mediated airway surface liquid regulation and identify potential cell and ion channel targets for therapeutic treatment of common airway diseases.