The Role of Airway Surface Liquid Nucleotides/Nucleosides in Volume Homeostasis

气道表面液体核苷酸/核苷在容量稳态中的作用

• 批准号: 8021819
• 负责人: Richard Charles Boucher
• 金额: $ 49.64万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8021819
• 关键词: Acute; Adenosine; Adhesions; Affinity; Anions; Asthma; Biochemical; Breathing; Cations; Characteristics; Chronic Obstructive Airway Disease; Complex; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Disease; Enzymes; Epithelial; Epithelium; Equilibrium; Gene Targeting; Genetic; Goals; Health; Homeostasis; Host Defense; Human; Hydration status; In Vitro; Infection; Ion Channel; Ion Transport; Ions; Isotonic Exercise; Knowledge; Ligands; Liquid substance; Lung; Lung diseases; Measures; Mediating; Metabolic; Metabolism; Modeling; Mucous body substance; Mus; Nucleosides; Nucleotides; Outcome; Pathogenesis; Patients; Peptide Hydrolases; Process; Public Health; Pump; Purine Nucleotides; Purinergic P2 Receptors; Purines; Purinoceptor; Receptor Activation; Regulation; Role; Signal Transduction; Sodium Chloride; Surface; System; Testing; Transgenic Mice; Transport Process; Water; absorption; airway epithelium; airway obstruction; airway surface liquid; apical membrane; bronchial epithelium; density; epithelial Na+ channel; extracellular; in vitro activity; in vivo; insight; mathematical model; mutant mouse model; network models; novel; novel therapeutics; pathogen; purine; research study; response; symporter; toxicant; vpr Genes

Control of airway surface liquid (ASL) volume is vital for pulmonary defense against inhaled pathogens/toxicants. Deficits in ASL volume produce airways obstruction and airways infection, reflecting the absence of periciliary liquid (PCL) volume and adhesion of dehydrated mucus to airway surfaces. Much is known about the ion transport processes that control transepithelial ion fluxes, but there are little or no data describing how these processes are coordinately regulated to adjust the mass of salt and, hence, water on airway surfaces in the ranges required for health. Studies of patients with genetic lung diseases, e.g., cystic fibrosis, have suggested that regulation of both the CFTR and ENaC channels are vital for this process. More recently, a number of clues have suggested a role for nucleotides (NTs) and nucleosides (NSs) in ASL in regulating the balance between Na+ absorption and Cl- secretion to generate ASL volume homeostasis. Indeed, we hypothesize that 1) ASL [NT+NS]s are so critical for ASL volume regulation that in their absence, airway epithelia revert to a purely Na+-absorbing state and deplete all ASL from airway surfaces; and 2) the volume of ASL is proportional to the rate of ATP release (JATP) onto airway surfaces. To test these hypotheses and generate a comprehensive description of ASL volume homeostasis, we propose three Specific Aims: 1) Aim 1 - measure JATP and extracellular NT+NS metabolism to develop a mathematical model that will integrate ASL NT+NS concentrations with a biophysical model of ion transport to describe the regulation of ASL volume homeostasis; 2) Aim 2 - test in human bronchial epithelial (HBE) cultures the requirement for NTs and NSs in the acute regulation of ASL volume homeostasis and the mechanisms that mediate these regulatory processes; and 3) Aim 3 - test the requirement for NT+NS in controlling ASL volume in mutant mouse models in vivo. Relevance to Public Health: Accurate quantitative knowledge of the factors that control ASL homeostasis, i.e., the 'hydration' of airway surfaces, will aid in elucidation of the pathogenesis of major human airways diseases, e.g., COPD, CF, and asthma, and will provide insights into novel therapeutic mechanisms to hydrate airway surfaces and hence, restore normal host defense.

控制气道表面液体（ASL）容量对于肺防御吸入性肺炎至关重要。 病原体/毒物。ASL容量的不足会导致气道阻塞和气道感染， 缺乏纤毛周围液体（PCL）体积和脱水粘液粘附到气道表面。多 已知控制跨上皮离子通量的离子转运过程，但很少或没有 描述这些过程如何协调调节以调整盐和水的质量的数据 在健康所需范围内的气道表面。对遗传性肺病患者的研究，例如， 囊性纤维化，表明CFTR和ENaC通道的调节对此至关重要 过程最近，一些线索表明核苷酸（NT）和核苷的作用 (NSs)在ASL中调节Na+吸收和Cl-分泌之间的平衡以产生ASL体积 体内平衡事实上，我们假设：1）ASL [NT+NS]对ASL容量调节至关重要， 当它们缺失时，气道上皮细胞恢复到纯Na+吸收状态，并耗尽气道中的所有ASL ASL的体积与气道表面的ATP释放速率（JATP）成正比。 为了验证这些假设并对ASL体积动态平衡进行全面描述，我们 提出了三个具体目标：1）目标1 -测量JATP和细胞外NT+NS代谢，以开发一种新的方法。 将ASL NT+NS浓度与离子转运的生物物理模型相结合的数学模型 描述ASL体积稳态的调节; 2）人支气管上皮（HBE）中的Aim 2 -测试 培养急性调节ASL容量稳态和 调节这些调节过程的机制;和3）目的3 -测试在哺乳动物中对NT+NS的需求。 控制体内突变小鼠模型中ASL体积。与公共卫生的相关性：准确的定量 了解控制ASL稳态的因素，即，气道表面的“水合作用”， 阐明了主要的人类气道疾病的发病机理，例如，COPD、CF和哮喘， 提供了新的治疗机制的见解，以水合气道表面，从而恢复正常 宿主防御