Ivacaftor for Acquired CFTR Dysfunction in Chronic Rhinosinusitis

Ivacaftor 治疗慢性鼻窦炎获得性 CFTR 功能障碍

• 批准号: 9324344
• 负责人: Bradford Alan Woodworth
• 金额: $ 36.65万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324344
• 关键词: 5' -AMP-activated protein kinase; Affect; Anions; Apical; Biological Assay; Biological Models; Cell Culture Techniques; Cell Wall; Cell surface; Cells; Chloride Channels; Chloride Ion; Chlorides; Chronic; Chronic Disease; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Disease; Epithelial; Epithelial Cells; Epithelium; Exposure to; Foundations; Functional disorder; Future; Generations; Gram-Negative Bacteria; Human; Hydrogen Peroxide; Impairment; In Vitro; Inflammation; Investigational Therapies; Ion Transport; Laboratories; Laboratory Finding; Lead; Lipopolysaccharides; Mass Spectrum Analysis; Maxillary Sinus; Maxillary Sinusitis; Measurement; Measures; Mediating; Modality; Modeling; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Mus; Nasal Epithelium; Nose; Oryctolagus cuniculus; Oxidants; PKA inhibitor; Pathogenesis; Patients; Pharmaceutical Preparations; Phosphorylation; Pilot Projects; Positioning Attribute; Pre-Clinical Model; Process; Proteins; Protocols documentation; Pseudomonas aeruginosa; Reactive Oxygen Species; Recycling; Refractory; Role; Scientist; Secondary to; Severity of illness; Sinus; Sinusitis; Structure; Superoxides; Surface; Surgeon; TLR4 gene; Testing; Therapeutic; Translating; Viscosity; chronic rhinosinusitis; clinically relevant; human subject; improved; in vivo; in vivo Model; indexing; inflammatory lung disease; kinase inhibitor; novel; novel therapeutic intervention; novel therapeutics; patch clamp; patient oriented research; pre-clinical; respiratory; standard care; therapy development; translational study

Ineffective mucociliary clearance (MCC) is a common pathophysiologic process contributing to chronic rhinosinusitis (CRS) - a highly prevalent disease with substantial morbidity. Evidence from our laboratory has demonstrated that brief exposures to lipopolysaccharide (LPS) from gram-negative bacteria lead to dysfunctional MCC by decreasing anion transport through CFTR apical Cl- channels in humans and other mammalian species. CFTR inhibition in this setting is caused by TLR4-mediated generation of reactive oxygen species (ROS), but independent of NFkB-derived inflammation. Furthermore, our group has confirmed the presence of acquired CFTR dysfunction in human sinuses, and has demonstrated that CFTR potentiators can stimulate Cl- secretion when partial CFTR dysfunction is present in multiple in vitro and preclinical models. Our central hypotheses are that LPS-induced acquired CFTR deficiency, 1) contributes substantially to the pathogenesis of CRS, and 2) can be treated with Ivacaftor, a CFTR potentiator developed for CF therapy. Specific Aim 1 will investigate the mechanistic basis of LPS-mediated CFTR dysfunction in sinonasal epithelium by 1) examining the oxidant-dependent inhibition of CFTR via AMP-dependent kinase (an inhibitor of PKA-dependent phosphorylation of the CFTR regulatory domain), 2) assessing the impact of ROS (superoxide, hydrogen peroxide) on CFTR function (patch clamp analysis) and structure (mass spectrometry), and 3) measuring the effects of longer exposures to LPS on CFTR expression, maturational processing, and recycling. Aim 2 will identify the efficiency of Ivacaftor in improving CFTR function in a pre-clinical rabbit model of acquired CFTR deficiency by 1) developing normative data for LPS-exposed rabbit maxillary sinus CFTR dysfunction, 2) assessing the effects of Ivacaftor on CFTR-related endpoints, and 3) evaluating Ivacaftor as therapy for Pseudomonas aeruginosa rabbit maxillary sinusitis. Aim 3 will conduct a clinical study using Ivacaftor in CRS patients by 1) correlating the novel “endoscopically-directed sinus potential difference” assay to validated measures of CRS disease severity and 2) performing a pilot clinical trial using Ivacaftor for CRS patients with refractory gram-negative bacterial CRS. The current proposal will help clarify mechanisms responsible for sinusitis pathogenesis, but also translates our laboratory findings to human subjects by providing a clinical trial using Ivacaftor for therapy of sinusitis. We believe our application will answer fundamental questions regarding pathomechanisms underlying CRS and establish the foundation for a new therapeutic approach to a serious and debilitating chronic disease.

无效的粘膜纤毛清除率（MCC）是一种常见的病理生理过程，导致慢性 鼻孔炎（CRS） - 一种高度流行的疾病，具有很大的发病率。我们实验室的证据 证明了革兰氏阴性细菌对脂多糖（LPS）的短暂暴露导致 通过减少通过CFTR顶端CL通道的阴离子转运的MCC功能失调的MCC 哺乳动物。在这种情况下，CFTR抑制是由TLR4介导的活性氧引起的 物种（ROS），但与NFKB衍生的炎症无关。此外，我们的小组已确认 在人类鼻窦中存在获得的CFTR功能障碍，并证明CFTR电势可以 当部分CFTR功能障碍以多种体外和临床前模型显示时，刺激CL分泌。我们的 中心假设是LPS诱导的CFTR缺乏症，1）对 CRS的发病机理和2）可以用ivacaftor处理，这是为CF开发的CFTR电位器 治疗。具体目标1将研究鼻窦中LPS介导的CFTR功能障碍的机理基础 1）通过AMP依赖性激酶（抑制剂）检查CFTR的氧化物依赖性抑制 CFTR调节域的PKA依赖性磷酸化），2）评估ROS的影响 （超氧化物，过氧化氢）在CFTR功能（斑块夹分析）和结构（质谱法）上， 3）测量较长暴露于LPS对CFTR表达，成熟处理和 回收。 AIM 2将确定ivacaftor在改善临床前兔模型中CFTR功能方面的效率 通过1）为LPS暴露于LPS暴露的兔上颌窦CFTR开发正常数据的CFTR缺乏症 功能障碍，2）评估ivacaftor对CFTR相关终点的影响，3）将Ivacaftor评估为 铜绿假单胞菌兔上颌鼻窦炎的治疗。 AIM 3将使用 CRS患者的ivacaftor通过1）将新型的“内镜下鼻窦电势差”测定 验证了CRS疾病严重程度的衡量标准和2）使用iVacafter进行CRS进行试验临床试验 难治性革兰氏阴性细菌CRS的患者。当前的建议将有助于确定机制 负责鼻窦炎发病机理，但也将我们的实验室发现转化为人类受试者 使用ivacafter提供临床试验来治疗鼻窦炎。我们相信我们的申请会回答 有关CRS基础病理机理的基本问题，并为新的基础建立了基础 严重且使人衰弱的慢性病的治疗方法。