ELECTROLYTE COMPOSITION OF SURFACE FLUID IN NORMAL AND CF AIRWAY EPITHELIA

正常和 CF 气道上皮表面液体的电解质组成

• 批准号: 6668332
• 负责人: Joseph Zabner
• 金额: $ 24.35万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6668332
• 关键词: Macaca mulatta; antibacterial agents; bactericidal immunity; body fluids; chloride channels; clinical research; cyclic AMP; cystic fibrosis; dogs; electrolyte balance; exocrine glands; ferrets; human subject; laboratory mouse; radiotracer; respiratory epithelium; secretion; secretory immune system; sheep; sodium channel; sodium chloride; swine; tissue /cell culture; transfection

(Adapted from the applicant's abstract) The investigators recently proposed a hypothesis to link the molecular and physiologic defect in CF, loss of CFTR C1- channel function and defective transepithelial C1- transport, with the clinical hallmark of CF, airway infections. They and others found that both normal and CF airway epithelia secrete antibacterial substances into the thin layer of fluid covering the apical surface. However the killing activity of these factors require a low NaC1 concentration. Reports that CF surface fluid has a high NaC1 concentration would explain the lack of bacterial killing in CF. They will test three hypotheses about the electrolyte composition of airway surface fluid. First, the salt concentration of airway surface fluid is increased in CF. To test this hypothesis investigators will use primary cultures of normal and CF airway epithelia to measure ion concentrations of ASF, as well as in vivo measurements done in animals and humans. Second, the increase in ASF salt concentration in CF is due to impaired electrolyte absorption. They will test the hypothesis by asking how normal and CF epithelia modify the electrolyte composition of ASF. Third, interventions that decrease salt concentration will restore bactericidal activity. To test this hypothesis they will restore CFTR function by gene transfer, activate alternative (non-CFTR) C1 channels and block epithelial Na+ channels. Investigators will also attempt to use novel approaches to decrease the concentration of salt in ASF. Given its importance, it is surprising that the composition of ASF is not better understood. The studies proposed should provide new insight into the electrolyte concentration of ASF and how they are modified. The results are central to understanding how the lack of CFTR C1- channels causes CF lung disease and to develop new therapies.

（改编自申请人摘要）研究人员最近提出了一项 将CF中的分子和生理缺陷、CFTR的丧失 C1通道功能和跨上皮C1转运缺陷， CF的临床特征，呼吸道感染。他们和其他人发现， 正常和CF气道上皮细胞分泌抗菌物质进入薄 覆盖顶端表面的液体层。然而， 这些因素需要低的NaCl浓度。报告称CF表面流体 具有高NaCl浓度可以解释细菌缺乏杀伤力， 参见 他们将检验关于气道电解质组成的三个假设， 表面流体首先，气道表面流体的盐浓度是 增加了CF。为了验证这一假设，研究人员将使用主要的 培养正常和CF气道上皮细胞，以测量 ASF，以及在动物和人类中进行的体内测量。二是 CF中ASF盐浓度增加是由于电解质受损 吸收他们将通过询问正常和CF 上皮细胞改变ASF的电解质组成。第三，干预措施 降低盐浓度将恢复杀菌活性。测试 这一假设，他们将恢复CFTR功能的基因转移，激活 替代（非CFTR）C1通道和阻断上皮Na+通道。 研究人员还将尝试使用新的方法来减少 ASF中盐的浓度。 鉴于其重要性，令人惊讶的是，ASF的组成并不 更好地理解。拟议的研究应提供新的见解， ASF的电解质浓度以及它们如何被修改。结果 理解CFTR C1通道的缺乏如何导致CF肺的核心 疾病和开发新的治疗方法。