Chloride secretagogues for acquired CFTR dysfunction in chronic rhinosinusitis

氯化物促分泌剂治疗慢性鼻窦炎获得性 CFTR 功能障碍

• 批准号: 8028013
• 负责人: Bradford Alan Woodworth
• 金额: $ 13.36万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8028013
• 关键词: Affect; Anions; Anti-Inflammatory Agents; Anti-inflammatory; Attention; Bioflavonoid; Biological Assay; Cell Wall; Chemosensitization; Chloride Ion; Chlorides; Chronic; Clinical; Clinical Research; Clinical Trials; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Disease; Drug Formulations; Electrolytes; Environment; Epithelial; Epithelium; Etiology; Expenditure; Exposure to; Foundations; Frequencies; Functional disorder; Future; Genetic Transcription; Health; Healthcare; Homeostasis; Human; Hypoxia; In Vitro; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Investigational Therapies; Ion Transport; Laboratories; Lipopolysaccharides; Liquid substance; Lung diseases; Maintenance; Measures; Mediating; Mediator of activation protein; Modality; Modeling; Morbidity - disease rate; Mucociliary Clearance; Mucositis; Mucous Membrane; Mucous body substance; Nasal Epithelium; Nitrogen; Nose; Oxygen; Pathway interactions; Patients; Population; Positioning Attribute; Process; Protein Biochemistry; Quality of life; Repression; Research; Role; Secondary to; Sinus; Sinusitis; Staging; Structure of respiratory epithelium; Testing; Therapeutic; Tissues; VX-770; Viscosity; airway inflammation; airway surface liquid; antimicrobial; base; chronic rhinosinusitis; cigarette smoking; economic impact; improved; in vivo; innovation; novel; novel therapeutics; patch clamp; research study; respiratory; response; treatment strategy

DESCRIPTION (provided by applicant): Ineffective mucociliary clearance (MCC) is a common pathophysiologic process that underlies airway inflammation and infection. Decreased transepithelial Cl- transport secondary to an acquired Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) deficiency may contribute to respiratory epithelial dysfunction by abrogating MCC and increasing mucus viscosity. The central hypothesis of the current proposal is that persistent mucosal inflammation and infection in chronic rhinosinusitis (CRS) results from acquired (partial) CFTR deficiency, creating a localized environment that impairs MCC. This hypothesis will be tested with three Specific Aims. Specific Aim 1 will investigate CFTR deficiency in a well-characterized in vitro culture model of sinonasal epithelium. Our Preliminary Data indicate that lipopolysaccharide not only promotes inflammation, but leads to CFTR repression in sinonasal epithelium. CFTR transcription, maturational processing (protein biochemistry), and channel potentiation (patch clamp analysis) will be used to determine the mechanism underlying this observation. Specific Aim 2 will test the hypothesis that Cl- secretagogues can offset acquired defects in CFTR-mediated ion transport. Compounds of this class, including VX-770, UCCF-152, and bioflavonoids have received considerable recent attention in both the scientific and lay press for their emerging role in cystic fibrosis (CF) therapeutics. We will investigate whether Cl- secretagogues 1) overcome acquired CFTR defects and 2) stimulate MCC (measured by ciliary beat frequency). Specific Aim 3 will determine the extent of acquired CFTR deficiency in human CRS ex vivo and in vivo. Transepithelial ion transport will be quantified in sinus mucosal explants in the Ussing chamber and in vivo, using a well established nasal potential difference assay. The proposal will therefore develop an innovative approach to better understand the pathogenic mechanisms of CRS, a disease understudied in the past, and develop an entirely novel treatment strategy for sinus and nasal airway disease predicated on activation of fluid and electrolyte secretion with leading edge Cl- secretagogues. PUBLIC HEALTH RELEVANCE: Chronic rhinosinusitis (CRS) affects nearly 16% of the US population each year, has an enormous economic impact resulting in billions of dollars in healthcare expenditures, and causes significant decrements in patient quality of life in terms of nasal airway specific morbidity, as well as general health and vitality. Because treatment options for CRS are usually limited to antimicrobials and anti-inflammatories, the research presented in this proposal provides a means to understand the pathogenic mechanism underlying CRS, and a new therapeutic strategy for restoring and/or increasing CFTR activity in sinus and nasal epithelium.

描述（由申请人提供）：无效的粘液纤毛清除（MCC）是气道炎症和感染的常见病理生理过程。继发性囊性纤维化跨膜电导调节器 (CFTR) 缺陷导致的跨上皮 Cl- 转运减少可能通过消除 MCC 和增加粘液粘度而导致呼吸道上皮功能障碍。当前提案的中心假设是，慢性鼻窦炎 (CRS) 中的持续粘膜炎症和感染是由获得性（部分）CFTR 缺陷引起的，从而产生了损害 MCC 的局部环境。该假设将通过三个具体目标进行检验。具体目标 1 将在特征明确的鼻窦上皮体外培养模型中研究 CFTR 缺陷。我们的初步数据表明，脂多糖不仅会促进炎症，还会导致鼻窦上皮细胞中 CFTR 的抑制。 CFTR 转录、成熟加工（蛋白质生物化学）和通道增强（膜片钳分析）将用于确定该观察结果的机制。具体目标 2 将检验以下假设：Cl-促分泌剂可以抵消 CFTR 介导的离子运输中的后天缺陷。此类化合物，包括 VX-770、UCCF-152 和生物类黄酮，因其在囊性纤维化 (CF) 治疗中的新兴作用，最近在科学界和非专业媒体中受到了相当多的关注。我们将研究 Cl-促分泌剂是否 1) 克服获得性 CFTR 缺陷和 2) 刺激 MCC（通过纤毛跳动频率测量）。具体目标 3 将确定人类 CRS 离体和体内获得性 CFTR 缺陷的程度。将使用完善的鼻电位差测定法对尤斯室和体内的鼻窦粘膜外植体中的跨上皮离子转运进行量化。因此，该提案将开发一种创新方法，以更好地了解 CRS（一种过去未得到充分研究的疾病）的致病机制，并开发一种全新的治疗策略，用于治疗鼻窦和鼻气道疾病，其基础是用领先的 Cl-促泌剂激活液体和电解质分泌。 公共健康相关性：慢性鼻窦炎 (CRS) 每年影响近 16% 的美国人口，产生巨大的经济影响，导致数十亿美元的医疗保健支出，并导致患者的鼻气道特定发病率以及总体健康和活力方面的生活质量显着下降。由于 CRS 的治疗选择通常仅限于抗菌药物和抗炎药物，因此本提案中提出的研究提供了一种了解 CRS 致病机制的方法，以及恢复和/或增加鼻窦和鼻上皮 CFTR 活性的新治疗策略。