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并影响 ~20% 的青少年和 >40% 的成人患有 CF。高效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。 然而，爱尔兰ivacaftor队列的随访显示，>18岁组的FEV1在治疗后仍然下降 初始增加（不区分患有和不患有 CFRD 的患者）。这与调查结果相反 FEV1 持续上升的年轻化阶段。由于 CFRD 的患病率随着年龄的增长而增加，我们想知道 服用 ivacaftor 的爱尔兰老年 CF 人群肺功能下降是否与 CFRD 有关。支持中 根据这一假设，我们的 CF 中心特定数据显示，服用 ivacaftor 的 CFRD 患者肺功能下降 与没有 CFRD 的患者相比，情况仍然更糟。因此，必须启动流行病学、机制和 血糖控制改变超出范围的 CF 患者肺功能保留的治疗研究 实现血糖正常并考虑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 产品（RAGE 或 AGER），在肺部高表达，与慢性疾病的发病机制有关 炎症性气道疾病，包括 CF。高血糖或 RAGE 激动剂高浓度激活 RAGE 流动性组盒-1 (HMGB1) 降低顶部表达的大电导、Ca2+ 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，被批准用于治疗糖尿病并已知可阻断 RAGE 信号传导， 逆转了 CFBE 细胞中高血糖诱导的 BK 功能障碍和 ASL 体积消耗，尽管持续 高血糖的存在。此外，二甲双胍改进了 elexacaftor/tezacaftor/ivacaftor 三联组合 - 介导高葡萄糖下 CFBE 细胞中 CFTR 功能和 ASL 体积的挽救。最后连续 对 CF 和 CFRD 患者的血糖水平进行为期一周的监测显示，高血糖 事件与 LRRC26 的 mRNA 表达呈负相关，LRRC26 是 BK 的 g 亚基，对其功能至关重要 非兴奋性细胞。因此，我们假设血糖异常的 CF 患者肺功能恶化 控制与 BK 相关，甚至与 RAGE 信号传导导致的调节剂挽救的 CFTR 功能障碍有关，并且 低剂量二甲双胍可改善 RAGE 诱导的离子通道功能障碍，包括存在以下情况时的 CFTR： 高效调节剂，独立于葡萄糖控制。我们将从机械和 体外（目标 1 和 2）和体内（目标 3）转化研究。