Mechanisms of mucociliary dysfunction in cystic fibrosis related diabetes

项目摘要/摘要 囊性纤维化(CF)相关性糖尿病(CFRD)是肺功能恶化的主要预测指标，并影响 约20%的青少年和40%的成年人患有CF。高效囊性纤维化跨膜电导 调节剂治疗可以改善患者的血糖控制，降低CFRD的患病率。 然而，爱尔兰iVacaftor队列的随访显示，18岁组的FEV1在治疗后仍有所下降 最初的增加(不区分患有和不患有CFRD的患者)。这与文献中的研究结果相反 FEV1持续上升的年轻人群。由于CFRD的患病率随着年龄的增长而增加，我们想知道 服用安慰剂的老年爱尔兰CF患者的肺功能是否下降可能与CFRD有关。在支持中 在这一假设下，我们的CF中心特有的数据显示，服用iVacaftor的CFRD患者的肺功能下降 仍然比没有CFRD的患者更糟糕。因此，当务之急是启动流行病学、机械性和 血糖控制异常的CF患者肺功能保护的治疗性研究 实现正常血糖，并考虑到高效调节剂的新时代。我们已经证明， 在CFBE细胞中，高血糖通过晚期糖基化终末受体发出信号 产物(RAGE或AGE)，它在肺中高表达，与慢性 炎症性呼吸道疾病，包括慢性阻塞性肺疾病。高血糖或RAGE激动剂HIGH激活RAGE 迁移率基团蛋白-1(HMGB1)降低顶端表达的大电导，钙激活， 电压依赖性K+(BK)通道和减少呼吸道表面液体(ASL)容量。临床水平较低，但相关 二甲双胍的浓度，被批准用于治疗糖尿病，已知可阻断RAGE信号， 逆转高血糖诱导的CFBE细胞BK功能障碍和ASL容量耗竭 存在高血糖。此外，二甲双胍改善了依拉卡福/替扎卡夫/异丙卡福三联用-- 高糖对CFBE细胞CFTR功能和ASL容量的调节作用最后，连续 对CFRD和CFRD患者一周的血糖水平监测显示，高血糖 发作与BK的g亚基LRRC26的mRNA表达呈负相关，LRRC26对BK的功能至关重要 不可兴奋的细胞。因此，我们假设伴有异常血糖的CF患者的肺功能恶化 控制与BK相关，甚至与RAGE信号导致的调节器挽救的CFTR功能障碍有关， 小剂量二甲双胍改善RAGE诱导的离子通道功能障碍，包括在 高效的调节剂，独立于血糖控制。我们将在机械和机械方面检验这一假设 体外翻译研究(目标1和2)和体内翻译研究(目标3)。

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).