Mechanisms of mucociliary dysfunction in cystic fibrosis related diabetes

囊性纤维化相关糖尿病粘膜纤毛功能障碍的机制

• 批准号: 10212505
• 负责人: MICHAEL D KIM
• 金额: $ 66.99万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212505
• 关键词: 18 year old; Adolescent; Adult; Affect; Age; Agonist; Airway Disease; Apical; CLCA2 gene; Cells; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Core-Binding Factor; Cultured Cells; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Diabetes Mellitus; Dose; Double-Blind Method; Epidemiology; Epithelial Cells; Feedback; Ferrets; Foundations; Functional disorder; Glucose; HMGB1 Protein; Hydration status; Hyperglycemia; In Vitro; Inflammation; Inflammatory; Ion Channel; Ligands; Link; Lung; MAP Kinase Gene; Measures; Mediating; Messenger RNA; Metformin; Molecular; Mucous body substance; Mutate; Nose; Nuclear; Obstruction; Outcome; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Population; Prevalence; Pulmonary Cystic Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Randomized; Recovery; Reporting; Signal Pathway; Signal Transduction; Structure; Testing; Therapeutic Studies; Transcription Factor AP-1; airway epithelium; airway surface liquid; blood glucose regulation; bronchial epithelium; clinically relevant; cohort; cystic fibrosis patients; cystic fibrosis related diabetes; data registry; follow-up; functional decline; glucose monitor; glycemic control; improved; improved functioning; in vivo; injured airway; large-conductance calcium-activated potassium channels; mRNA Expression; mRNA Precursor; mucus clearance; mutant; negative affect; p38 Mitogen Activated Protein Kinase; patient registry; pre-clinical; preservation; pulmonary function; pulmonary function decline; receptor; receptor for advanced glycation endproducts; soluble RAGE; translational study; voltage

Project Summary/Abstract Cystic fibrosis (CF)-related diabetes mellitus (CFRD) is a major predictor of worse lung function and affects ~20% of adolescents and >40% of adults with CF. Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies can improve glycemic control in patients and reduce prevalence of CFRD. However, the follow up of the Irish ivacaftor cohort shows that FEV1 in the >18-year old group still declines after an initial increase (not distinguishing between patients with and without CFRD). This is opposed to findings in younger ages where FEV1 continues to rise. Since prevalence of CFRD increases with age, we wondered whether lung function decline in the older Irish CF population on ivacaftor could be related to CFRD. In support of this hypothesis, our CF center-specific data show that lung function decline in patients on ivacaftor with CFRD remains worse than in patients without CFRD. Thus, it is imperative to initiate epidemiological, mechanistic, and therapeutic studies on lung function preservation in CF patients with altered glucose control that go beyond achieving normoglycemia and take the new era of highly effective modulators into account. We have shown that, in CF bronchial epithelial (CFBE) cells, hyperglycemia signals through the receptor for advanced glycation end products (RAGE or AGER), which is highly expressed in the lung and linked to the pathogenesis of chronic inflammatory airway diseases, including CF. Activation of RAGE by hyperglycemia or the RAGE agonist high- mobility group box-1 (HMGB1) decreases the activity of apically expressed large-conductance, Ca2+-activated, voltage-dependent K+ (BK) channels and reduces airway surface liquid (ASL) volume. Clinically low but relevant concentrations of metformin, approved for treating diabetes mellitus and known to block RAGE signaling, reversed hyperglycemia-induced BK dysfunction and ASL volume depletion in CFBE cells despite the continued presence of high glucose. Furthermore, metformin improved elexacaftor/tezacaftor/ivacaftor triple combination- mediated rescue of CFTR function and ASL volumes in CFBE cells under high glucose. Finally, continuous monitoring of glucose levels in CF and CFRD patients over a one-week period revealed that hyperglycemic episodes inversely correlated with mRNA expression of LRRC26, the g subunit of BK critical for its function in non-excitable cells. We therefore hypothesize that worsening lung function in CF patients with abnormal glucose control is associated with BK and even modulator-rescued CFTR dysfunction due to RAGE signaling and that low dose metformin ameliorates RAGE-induced ion channel dysfunction, including CFTR in the presence of highly effective modulators, independent of glucose control. We will test this hypothesis in mechanistic and translational studies in vitro (Aims 1 and 2) and in vivo (Aim 3).

项目摘要/摘要 囊性纤维化（CF）相关糖尿病（CFRD）是肺功能较差的主要预测指标，并影响 约有20％的青少年和> 40％的成年人患有CF。高效的囊性纤维化跨膜电导 调节剂（CFTR）调节剂疗法可以改善患者的血糖控制并降低CFRD的患病率。 但是，爱尔兰ivacaftor队列的随访表明，> 18岁的小组的FEV1在 初始增加（没有区分和没有CFRD的患者）。这反对 FEV1继续上升的年轻人。由于CFRD的患病率随着年龄的增长而增加，我们想知道 ivacaftor上年长的爱尔兰CF人群的肺功能是否可能与CFRD有关。支持 在这个假设中，我们的CF中心特异性数据表明，ivacaftor患者的肺功能下降 比没有CFRD的患者还要糟糕。因此，必须启动流行病学，机械和 葡萄糖控制改变的CF患者肺功能保存的治疗研究超出 实现正常血糖并考虑了高效调节剂的新时代。我们已经表明， 在CF支气管上皮（CFBE）细胞中，通过受体进行高血糖信号以进行晚期糖基化末端 产物（愤怒或Ager），该产品在肺部高度表达，与慢性发病机理有关 炎症性气道疾病，包括参见。高血糖或愤怒的激动剂高 - 激活愤怒 Mobility of box-1（HMGB1）降低了顶尖表达的大传导性的活性，Ca2+激活， 依赖电压的K+（BK）通道并减少气道表面液体（ASL）体积。临床低但相关 二甲双胍的浓度，批准用于治疗糖尿病的含量，已知可以阻止愤怒信号传导， 尽管持续 高葡萄糖的存在。此外，二甲双胍改善了Elexacaftor/tezacaftor/ivacaftor三重组合 - 在高葡萄糖下介导的CFTR功能和CFBE细胞中ASL体积的拯救。最后，连续 在一个星期内监测CF和CFRD患者中的葡萄糖水平，发现高血糖 发作与LRRC26的mRNA表达成反比，BK的g亚基对其在功能中的功能至关重要 不可驱行的细胞。因此，我们假设CF异常葡萄糖患者的肺功能恶化 控制与BK甚至调节器验证的CFTR功能障碍有关，并且由于愤怒信号传导而与 低剂量二甲双胍可以改善愤怒诱导的离子通道功能障碍，包括在存在的情况下CFTR 高效的调节剂，独立于葡萄糖控制。我们将在机械和 体外翻译研究（目标1和2）和体内（AIM 3）。