Ion Transport in Alveolar Type I Cells

I 型肺泡细胞中的离子传输

基本信息

批准号：
7599513
负责人：
MESHELL JOHNSON
金额：
$ 9.53万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7599513
关键词：
Active Ion Transport Acute Lung Injury Acute Pneumonia Address Adenosine Adult Adult Respiratory Distress Syndrome Affect Agonist Alveolar Alveolar Cell Type I Amiloride Anions Apical Area Biochemical Cardiovascular system Carrier Proteins Cells Commit Communities Cyclic AMP Cyclic Nucleotides Cystic Fibrosis Transmembrane Conductance Regulator Data Development Plans Disease Environment Epithelial Epithelial Cells Epithelium Failure Floods Fluid Balance Future Gases Glucocorticoids Goals Homeostasis Human Ion Channel Ion Transport Ions Kidney Liquid substance Lung Measures Mediating Medicine Modality Molecular Movement Na(+)-K(+)-Exchanging ATPase Nitric Oxide Pathway interactions Physicians Play Production Publishing Pulmonary Edema Pulmonary alveolar structure Pulmonology Rattus Regulation Reporting Research Research Institute Research Personnel Resources Role Route Scientist Sensory Site Surface Techniques Training Type I Epithelial Receptor Cell Type II Epithelial Receptor Cell Ubiquitin Water Work absorption alveolar epithelium career career development cell type cyclic-nucleotide gated ion channels design driving force epithelial Na+ channel inhibitor/antagonist insight multicatalytic endopeptidase complex novel patch clamp prevent programs research study solute theories therapeutic development therapy development uptake water channel

项目摘要

DESCRIPTION (provided by applicant): Fluid balance in the lung is critical to survival. One million people are hospitalized each year for pneumonia, acute lung injury, or acute respiratory distress syndrome, diseases which compromise oxygenation from the failure of gas exchange in the lungs due to alveolar flooding. Alveolar fluid clearance is driven by active ion transport across the alveolar epithelium, composed of type I cells, which cover > 95% of the internal surface area of the lung, and type II cells, which line ~5%. The generally accepted theory of ion and fluid transport in the lung is that type II cells, known to contain ion transport proteins, govern alveolar fluid balance by regulating Na+ transport, while type I cells, which contain water channels, merely provide a route for passive water absorption. However, the extensive alveolar surface area occupied by type I cells suggests that these cells may play a larger role in regulating lung fluid balance. Our preliminary data demonstrate that there are functional ion channels in type I cells, and that there are significant differences in how Na+ and Cl- transport are regulated in type I and type II cells. The underlying hypotheses for the studies in this application are that ion transport in type I and type II cells is regulated in part by different mechanisms and that the effects of agents that modulate alveolar fluid clearance in whole lungs are better explained by the effects of these agents on type I, rather than type II, cells. Specific Aim 1 will determine regulatory mechanisms of Na+ transport in type I cells by studying modulation of ENaC and Na+-, K+-ATPase. Specific Aim 2 will explore mechanisms of amiloride-insensitive Na+ transport in type I cells. Specific Aim 3 willstudy anion transport in type I cells and determine the roles of adenosine and beta-agonists on Cl- flux regulation. Elucidating the mechanisms of lung fluid homeostasis will be invaluable in developing strategies to treat alveolar flooding, as such therapies do not currently exist. The UCSF Department of Medicine and the Cardiovascular Research Institute provide ideal settings for training physician-scientists, combining multiple resources and a scientific community that is committed and excited about training future academic researchers. This proposal will develop expertise in ion transport in alveolar type I cells with the ultimate objective of clarifying how the lungs regulate lung fluid balance. The research and career development plan will aid in the candidate's goal to become an independent investigator with an academic career in Pulmonary Medicine.

描述（由申请人提供）：肺内的液体平衡对于生存至关重要。每年有一百万人因肺炎、急性肺损伤或急性呼吸窘迫综合征而住院，这些疾病会因肺泡充盈导致肺部气体交换失败而损害氧合。肺泡液清除是由跨肺泡上皮的活性离子传输驱动的，肺泡上皮由 I 型细胞和 II 型细胞组成，I 型细胞覆盖肺内表面积的 95% 以上，而 II 型细胞则覆盖约 5%。肺中离子和液体运输的普遍接受的理论是，已知含有离子运输蛋白的 II 型细胞通过以下方式控制肺泡液体平衡：调节Na+运输，而含有水通道的I型细胞仅提供被动的途径吸水率。然而，I 型细胞占据的广泛肺泡表面积表明这些细胞可能在调节肺液平衡方面发挥更大的作用。我们的初步数据表明，有 I 型细胞中的功能性离子通道，Na+ 和 Cl- 的转运方式存在显着差异在 I 型和 II 型细胞中受到调节。本申请研究的基本假设是 I 型和 II 型细胞中的离子转运部分受到不同机制的调节，并且调节整个肺部肺泡液清除率的药物可以通过这些药物的作用得到更好的解释药物作用于 I 型细胞，而不是 II 型细胞。具体目标 1 将确定 Na+ 的调节机制通过研究 ENaC 和 Na+-、K+-ATPase 的调节来实现 I 型细胞的转运。具体目标2将探讨 I 型细胞中阿米洛利不敏感的 Na+ 转运机制。具体目标 3 将研究阴离子转运 I 型细胞并确定腺苷和β-激动剂对 Cl-通量调节的作用。阐明肺液稳态机制对于制定治疗肺泡溢流的策略将具有无价的价值，因为目前尚不存在此类疗法。加州大学旧金山分校医学与心血管研究系研究所为培训医师科学家提供了理想的环境，结合了多种资源和科学致力于并热衷于培训未来学术研究人员的社区。该提案将发展 I 型肺泡细胞离子转运方面的专业知识，最终目标是阐明肺如何调节肺液平衡。研究和职业发展计划将有助于候选人实现以下目标：成为一名独立研究者，从事肺科医学的学术生涯。