Regulation of Lung Sodium Channels

肺钠通道的调节

• 批准号: 7867963
• 负责人: LUCKY JAIN
• 金额: $ 38.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867963
• 关键词: Adrenergic Agents; Alveolar; Alveolar Cell; Alveolus; Amiloride; Anions; Area; Biochemical; Biological; Cations; Cells; Characteristics; Clinical Trials; Complement; Coupled; Cyclic AMP; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Disease; Distal; Dopamine D1 Receptor; Dopamine Receptor; Environment; Epithelial; Epithelial Cells; Epithelium; Fluid Balance; Goals; Grant; Homeostasis; Hormonal; Investigation; Ion Channel; Ion Transport; Laboratories; Lead; Link; Liquid substance; Lung; Methods; Molecular; Nephrons; Patch-Clamp Techniques; Pathway interactions; Phenotype; Phosphotransferases; Play; Potassium Channel; Process; Property; Proteins; Pulmonary Edema; Rana; Regulation; Research Personnel; Role; Signal Pathway; Signal Transduction; Skin; Sodium; Sodium Channel; Sodium Chloride; Steroids; Stimulus; Surface; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Ursidae Family; Water; Work; absorption; adrenergic; alveolar epithelium; apical membrane; cell type; cyclic-nucleotide gated ion channels; density; design; epithelial Na+ channel; interest; prevent; programs; receptor; research study; respiratory distress syndrome; response; solute

DESCRIPTION (provided by applicant): Fluid homeostasis in the alveolar spaces is maintained by osmotic gradients created by active solute transport via epithelial cells. Abnormalities of solute transport have been implicated in several disease states including respiratory distress syndrome and cystic fibrosis. Transport of sodium through channels located in the apical membranes of alveolar epithelial cells is believed to be the initial and rate limiting step in salt absorption by these tissues. These channels can be found in many vertebrate epithelial tissues ranging from frog skin to mammalian distal nephron. In contrast to a well described role for alveolar type 2 (AT2) cells in lung ion transport, evidence for a definite role for alveolar type 1 (AT1) cells is lacking. The long-term goal of this project is to compare and contrast ion transport by the two epithelial cell types. Preliminary experiments from this laboratory show that AT1 cells express at least three distinct types of cation channels that are capable of transporting sodium. The biophysical characteristics bear some similarities to the channels observed in AT2 cells and other tight epithelia expressing epithelial sodium channel (ENaC). However, there may be important differences in how these channels are regulated in AT1 and AT2 cells, and additional transporters in AT1 cells that are not readily seen in AT2 cells. These findings support a radically different paradigm for salt and water transport in the lung. The primary hypothesis is that AT1 cells make significant contribution to alveolar solute transport via amiloride-sensitive channels, albeit by a different mechanism as compared to AT2 cells. Despite the differences in biophysical characteristics, sodium permeable channels in AT1 cells are assembled from different ENaC subunits and this process is regulated in part by the alveolar environment: It is also hypothesized that significant differences exist in the regulatory mechanisms for solute transport by AT1 and AT2 cells. The specific aims are: 1) To characterize and contrast the biophysical properties of ion channels in AT1 and AT2 cells at the single channel level, and 2) To examine differences in how these channels are regulated in the two cell types and what impact they have on net salt and water transport in the lung. An understanding of these differences is essential for estimating the overall response of lungs to endogenous and exogenous stimuli that have the potential for altering lung fluid balance, and ultimately, in designing therapeutic strategies to prevent and treat lung edema formation.

描述（由申请人提供）：肺泡腔中的液体稳态是通过上皮细胞的活性溶质转运产生的渗透梯度来维持的。溶质转运异常与多种疾病状态有关，包括呼吸窘迫综合征和囊性纤维化。通过位于肺泡上皮细胞顶膜的通道转运钠被认为是这些组织吸收盐的初始步骤和速率限制步骤。这些通道可以在从青蛙皮肤到哺乳动物远端肾单位的许多脊椎动物上皮组织中找到。与已充分描述的 2 型肺泡 (AT2) 细胞在肺离子转运中的作用相反，缺乏 1 型肺泡 (AT1) 细胞明确作用的证据。该项目的长期目标是比较和对比两种上皮细胞类型的离子转运。该实验室的初步实验表明，AT1 细胞表达至少三种不同类型的能够运输钠的阳离子通道。其生物物理特征与在 AT2 细胞和其他表达上皮钠通道 (ENaC) 的紧密上皮细胞中观察到的通道有一些相似之处。然而，这些通道在 AT1 和 AT2 细胞中的调节方式可能存在重要差异，并且 AT1 细胞中的其他转运蛋白在 AT2 细胞中不容易看到。这些发现支持了肺部盐和水运输的完全不同的范例。主要假设是 AT1 细胞通过阿米洛利敏感通道对肺泡溶质转运做出了重大贡献，尽管与 AT2 细胞相比，其机制不同。尽管生物物理特性存在差异，但 AT1 细胞中的钠渗透通道是由不同的 ENaC 亚基组装而成，并且该过程部分受到肺泡环境的调节：还假设 AT1 和 AT2 的溶质转运调节机制存在显着差异细胞。具体目标是：1) 在单通道水平上表征和对比 AT1 和 AT2 细胞中离子通道的生物物理特性，以及 2) 检查这些通道在两种细胞类型中的调节方式的差异及其产生的影响影响肺部净盐和水的运输。了解这些差异对于估计肺部对可能改变肺液平衡的内源性和外源性刺激的总体反应至关重要，并最终设计预防和治疗肺水肿形成的治疗策略。