Chloride secretagogues for acquired CFTR dysfunction in chronic rhinosinusitis

描述（由申请方提供）：无效粘膜纤毛清除（MCC）是一种常见的病理生理过程，是气道炎症和感染的基础。继发于获得性囊性纤维化跨膜传导调节因子（CFTR）缺乏的跨上皮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。目前建议的中心假设是慢性鼻窦炎（CRS）中持续的粘膜炎症和感染是由获得性（部分）CFTR缺乏引起的，从而产生了损害MCC的局部环境。这一假设将通过三个具体目标进行检验。具体目标1将调查CFTR缺陷，在一个良好的特点，在体外培养模型的鼻窦上皮。我们的初步数据表明，脂多糖不仅促进炎症，但导致CFTR抑制在鼻窦上皮。CFTR转录、成熟加工（蛋白质生物化学）和通道增强（膜片钳分析）将用于确定这一观察结果的机制。具体目标2将检验Cl-促分泌素可以抵消CFTR介导的离子转运中的获得性缺陷的假设。这类化合物，包括VX-770、UCCF-152和联苯双酯，由于其在囊性纤维化（CF）治疗中的新兴作用，最近在科学界和新闻界都受到了相当大的关注。我们将研究Cl-促分泌素是否1）克服获得性CFTR缺陷和2）刺激MCC（通过纤毛搏动频率测量）。具体目标3将确定人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，在Ussing室和体内对窦粘膜外植体中的跨上皮离子转运进行定量。因此，该提案将开发一种创新方法，以更好地了解CRS（过去未充分研究的疾病）的致病机制，并开发一种全新的鼻窦和鼻气道疾病治疗策略，该策略基于使用前沿Cl-促分泌素激活液体和电解质分泌。 公共卫生相关性：慢性鼻窦炎（CRS）每年影响近16%的美国人口，具有巨大的经济影响，导致数十亿美元的医疗保健支出，并导致患者在鼻气道特异性发病率以及总体健康和活力方面的生活质量显著下降。由于CRS的治疗选择通常仅限于抗菌剂和抗炎剂，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。

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.