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）：肺泡空间中的流体稳态由通过上皮细胞主动溶质传输产生的渗透梯度维持。溶质运输的异常已与几种疾病状态有关，包括呼吸窘迫综合征和囊性纤维化。据信，钠通过位于肺泡上皮细胞顶端膜中的通道传输是这些组织吸收盐吸收盐的初始和速率限制步骤。这些通道可以在许多脊椎动物上皮组织中找到，从青蛙皮肤到哺乳动物远端肾脏。与肺离子传输中肺泡2（AT2）细胞的作用有充分描述的作用相反，缺乏证据表明肺泡1型（AT1）细胞的明确作用。该项目的长期目标是将两种上皮细胞类型进行比较和对比离子运输。该实验室的初步实验表明，AT1细胞至少表达能够运输钠的三种不同类型的阳离子通道。生物物理特征与在AT2细胞和其他表达上皮钠通道（ENAC）的紧密上皮中观察到的通道具有一些相似之处。但是，在AT1和AT2细胞中如何调节这些通道的方式可能存在重要差异，并且在AT2细胞中不容易看到的AT1细胞中的其他转运蛋白。这些发现支持肺中盐和水运输的根本不同的范式。主要的假设是，AT1细胞通过与AT2细胞相比，通过不同机制对通过艾米洛里德敏感的通道做出了重要贡献。尽管生物物理特性差异，但AT1细胞中的钠可渗透通道来自不同的ENAC亚基，并且该过程部分受肺泡环境调节：还可以假设，在AT1和AT2细胞中溶解的调节机制中存在显着差异。具体目的是：1）表征和对比单个通道水平的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如何调节这些通道的差异，以及它们对肺中净盐和水的影响。对这些差异的理解对于估计具有改变肺液平衡潜力的内源性和外源刺激的总体反应至关重要，最终在设计治疗策略方面预防和治疗肺水肿形成。