Regulation of lung epithelial sodium channels by cGMP

cGMP 对肺上皮钠通道的调节

基本信息

批准号：
7577411
负责人：
HONG-LONG JI
金额：
$ 27.5万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7577411
关键词：
Adult Alveolar Alveolar Cell Amiloride Amino Acids Arts Biochemical Biological Biotinylation Cations Cell surface Cells Confocal Microscopy Cyclic GMP Cyclic GMP-Dependent Protein Kinases Data Development Edema Electrodes Epithelial Epithelial Cells Gases Goals Heart Diseases Human Hydrostatic Pressure Ions Liquid substance Lung Maintenance Measures Mediating Molecular Mus Oocytes Patch-Clamp Techniques Pathway interactions Patients Permeability Physiological Plasma Proteins Probability Property Proteins Pulmonary Edema RNA Splicing Regulation Research Research Personnel Site Small Interfering RNA Sodium Channel Soluble Guanylate Cyclase Techniques Testing Time Transfection Variant Xenopus oocyte Zinc alveolar epithelium base combat depression epithelial Na+ channel fetal in vivo interest monolayer mutant novel therapeutics protein expression voltage clamp

项目摘要

DESCRIPTION (provided by applicant): In order for gas exchange to occur in an optimum fashion, the alveolar space must remain free of fluid. Convincing evidence indicates that active Na+ transport across the alveolar epithelium in vivo contributes to the reabsorption of the fetal fluid and to the maintenance of fluid free alveolar spaces in adult lungs, especially when either alveolar permeability to plasma proteins or lung hydrostatic pressures are increased. Na+ ion reabsorption occurs through the amiloride sensitive epithelial Na+ channels (((( ENaC) and poorly characterized cation channels. Based on the exciting preliminary data presented in this application, we hypothesize that a newly described protein (( ENaC) fundamentally alters the biophysical properties of ((( ENaC-type channels and renders them sensitive to regulation via the cGMP/PKG axis. The main goals of this application are: 1) to fully characterize the biophysical and pharmacological properties of ( ENaC type channels in both Xenopus oocytes and human lung epithelial cells; 2) to investigate the regulation of ( ENaC-containing channels by cGMP in oocytes and human alveolar cells; and 3) to assess the contribution of ( ENaC to vectorial Na+ transport across human epithelial cell monolayers mounted in Ussing chambers and mouse lungs in vivo using state-of-the-art biochemical, molecular biological, electrophysiological and physiological techniques. The following specific hypotheses will be tested: 1) ( ENaC-containing homo- and heteromeric channels expressed in Xenopus oocytes have diverse biophysical properties; 2) cGMP regulates (ENaC-containing homo- and heteromeric channels but not ((( channels expressed in Xenopus oocytes; and 3) ( ENaC contributes to the non-((( ENaC Na+ currents across primary human alveolar type II (ATII) and H441 monolayers and to alveolar fluid clearance in mouse lungs. The subject matter of this research is timely and important. Results of these studies may form the molecular basis for development of new therapeutic strategies (such as cGMP delivery) to combat pulmonary edema.

描述（由申请人提供）：为了使气体交换以最佳方式发生，牙槽空间必须没有流体。令人信服的证据表明，体内的主动Na+转运在胎儿液体中的重吸收和成年肺中液体不含肺泡的空间的维持，尤其是当肺泡渗透性对血浆蛋白或肺部水分压力增加时。 Na+ ion reabsorption occurs through the amiloride sensitive epithelial Na+ channels (((( ENaC) and poorly characterized cation channels. Based on the exciting preliminary data presented in this application, we hypothesize that a newly described protein (( ENaC) fundamentally alters the biophysical properties of ((( ENaC-type channels and renders them sensitive to regulation via the CGMP/PKG轴。使用最先进的生化，分子生物学，电生理学和生理技术的人体内安装在Ussing室和小鼠肺中的人类上皮细胞单层将被测试：1）（1）。 2）CGMP调节（含ENAC的同种和异源通道，但不是（（（（（（（（（（（在Xenopus卵母细胞中，通道）；和3）（ENAC有助于非 - （（（（（（（（（（（（（（（（（（（（（e，跨eNAC Na+电流）跨人类型人类肺泡II（ATII）和H4441单层和H4441单层的含量和Alve clever的研究结果。研究可能构成开发新的治疗策略（例如CGMP递送）以应对肺水肿的分子基础。