Chloride secretagogues for acquired CFTR dysfunction in chronic rhinosinusitis

描述（由申请人提供）：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剂（CFTR）缺乏的经上皮Cl-转运减少可能通过MCC的消失和黏液粘度的增加导致呼吸上皮功能障碍。当前建议的中心假设是慢性鼻窦炎（CRS）的持续粘膜炎症和感染是由获得性（部分）CFTR缺乏引起的，从而产生损害MCC的局部环境。这一假设将通过三个具体目标进行检验。特异性目的1将在具有良好特征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，脂多糖不仅促进炎症，而且导致鼻窦上皮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）将用于确定这一观察的机制。特异性目的2将验证Cl-分泌剂可以抵消cftr介导的离子运输中获得性缺陷的假设。这类化合物，包括VX-770、UCCF-152和生物类黄酮，由于其在囊性纤维化（CF）治疗中的新作用，最近在科学界和媒体上都受到了相当大的关注。我们将研究Cl-分泌剂是否1)克服获得性CFTR缺陷，2)刺激MCC（通过纤毛搏动频率测量）。特异性目标3将确定体外和体内人类CRS中获得性CFTR缺乏的程度。使用一种完善的鼻电位差测定法，将在Ussing室和体内的鼻窦粘膜外植体中量化经上皮离子转运。因此，该提案将开发一种创新的方法，以更好地了解CRS的致病机制，这是一种过去未被充分研究的疾病，并开发一种基于激活液体和电解质分泌的尖端Cl-分泌剂的鼻窦和鼻气道疾病的全新治疗策略。

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.