Chloride secretagogues for acquired CFTR dysfunction in chronic rhinosinusitis

描述(由申请人提供)：无效的粘液纤毛清除(MCC)是一种常见的病理生理过程，是呼吸道炎症和感染的基础。继发于获得性囊性纤维化跨膜电导调节器(CFTR)缺陷的跨上皮氯离子转运减少可能通过消除MCC和增加粘液粘度而导致呼吸上皮功能障碍。当前建议的中心假设是慢性鼻-鼻窦炎(CRS)的持续性粘膜炎症和感染是获得性(部分)CFTR缺陷的结果，创造了一种损害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将在一个特征良好的鼻窦上皮体外培养模型中调查CFTR缺陷。我们的初步数据表明，内毒素不仅促进炎症，而且导致鼻腔上皮细胞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)将被用来确定这一观察结果的机制。特定目标2将检验这一假设，即氯-促分泌剂可以抵消CFTR介导的离子运输中的获得性缺陷。这类化合物，包括VX-770、UCCF-152和生物黄酮类化合物，由于其在囊性纤维化(CF)治疗中的新作用，最近在科学界和公众中都受到了相当大的关注。我们将研究氯-促分泌剂是否1)克服获得性CFTR缺陷和2)刺激MCC(通过纤毛搏动频率测量)。特异靶3将确定获得性CFTR体内外人CRS缺陷的程度。在Ussing小室和活体内，将使用公认的鼻腔电势差分析来量化鼻窦黏膜植入物中跨上皮离子的传输。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，这是一种过去研究不足的疾病，并将开发一种全新的治疗策略，用于鼻窦和鼻呼吸道疾病，其基础是利用前沿的Cl-促分泌剂激活液体和电解质分泌。

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.