Mechanisms of mucociliary dysfunction in cystic fibrosis related diabetes

项目概要/摘要 囊性纤维化（CF）相关糖尿病（CFRD）是肺功能恶化的主要预测因素， 约20%的青少年和>40%的成年CF患者。高效囊性纤维化跨膜电导 CFTR调节剂治疗可以改善患者的血糖控制并降低CFRD的患病率。 然而，爱尔兰ivacaftor队列的随访显示，>18岁组中的FEV 1在 初始增加（不区分患有和不患有CFRD的患者）。这是反对调查结果， FEV 1持续上升的年龄较小。由于CFRD的患病率随着年龄的增长而增加，我们想知道 接受ivacaftor治疗的老年爱尔兰CF人群的肺功能下降是否与CFRD相关。支持 根据这一假设，我们的CF中心特异性数据显示，CFRD患者接受依伐卡托治疗后肺功能下降， 仍然比没有CFRD的患者更糟。因此，必须启动流行病学、机械学和 糖控制改变的CF患者肺功能保护的治疗研究， 实现正常的代谢，并考虑到高效调节剂的新时代。我们已经证明， 在CF支气管上皮（CFBE）细胞中，高血糖通过晚期糖基化末端受体发出信号， 在肺中高度表达并与慢性炎症的发病机制相关的蛋白质产物（AGER或AGER）。 炎症性气道疾病，包括CF。高血糖症或高血糖症激动剂激活β-淀粉样蛋白， 迁移率族蛋白盒-1（HMGB 1）降低了顶端表达的大电导，Ca 2+激活， 电压依赖性K+（BK）通道，并减少气道表面液体（ASL）量。临床低，但相关 二甲双胍的浓度，其被批准用于治疗糖尿病并且已知阻断β 2受体信号传导， 逆转高血糖诱导的BK功能障碍和ASL容量减少的CFBE细胞， 高葡萄糖的存在。此外，二甲双胍改善了elexacaftor/tezacaftor/ivacaftor三联组合- 在高葡萄糖下，CFBE细胞中CFTR功能和ASL体积的介导的拯救。最后，连续 对CF和CFRD患者一周内的血糖水平监测显示， 发作与LRRC 26的mRNA表达呈负相关，LRRC 26是BK的g亚基，在 非兴奋细胞因此，我们假设，血糖异常的CF患者的肺功能恶化 控制与BK相关，甚至与调节剂拯救的CFTR功能障碍有关， 低剂量二甲双胍可改善RAGE诱导的离子通道功能障碍，包括在 高效调节剂，不依赖于葡萄糖控制。我们将在机械和 体外（目标1和2）和体内（目标3）的翻译研究。

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).