Ion Transport in Alveolar Type I Cells

I 型肺泡细胞中的离子传输

• 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
• 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

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）：肺中的流体平衡对于生存至关重要。每年有100万人因肺炎，急性肺损伤或急性呼吸窘迫综合征住院，这会损害由于肺泡洪水导致的气体交换而导致肺部气体交换失败。肺泡流体清除率是由由I型细胞组成的肺泡上皮的活性离子转运驱动的，I型细胞覆盖了肺部内部表面积的95％，II型细胞占了约5％的II型细胞。肺中离子和液体转运的普遍接受理论是，II型细胞（已知包含离子转运蛋白）通过 调节Na+传输，而I型电池的I型单元仅提供了被动的途径 吸水。但是，由I型细胞占据的广泛的肺泡表面积表明这些表面 细胞在调节肺液平衡中可能起更大的作用。我们的初步数据表明有 I型细胞中的功能离子通道，Na+和Cl-转运的方式存在显着差异 在I型和II型细胞中进行调节。本应用程序中研究的基本假设是 I型和II型细胞中的离子运输部分由不同的机制调节，并且 通过这些作用更好地解释了调节整个肺肺泡液清除率的药物的影响 I型代理，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的调制，在I型细胞中运输。特定的目标2将探索 I型细胞中对Amiloride不敏感Na+转运的机制。特定的目标3威尔研究阴离子在 I型细胞并确定腺苷和β-激动剂在Clux调节中的作用。阐明 肺液体稳态机制对于制定治疗肺泡洪水的策略将是无价的，因为 这种疗法目前不存在。 UCSF医学系和心血管研究 研究所为培训医师科学家提供理想的环境，结合多个资源和科学 致力于培训未来学术研究人员的社区。该提议将 在牙槽I型细胞中发展离子传输方面的专业知识，其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的目标 成为具有肺医学学术生涯的独立研究者。