Altered Circadian Rhythm Regulation in Cystic Fibrosis

虽然囊性纤维化(CF)患者以呼吸系统和消化系统疾病为主 发病率和死亡率的来源还有许多其他临床相关症状，如 抑郁和焦虑，睡眠质量差，包括睡眠障碍和睡眠改变 模式。慢性阻塞性肺疾病患者经历的睡眠障碍与昼夜节律一致 节奏(CR)相位延迟。慢性阻塞性肺疾病患者CR与睡眠调节的临床相关性 研究表明睡眠质量较差的慢性阻塞性肺疾病患者有更严重的肺部疾病 随着时间的推移，结果会越来越差。CF的CR中断是否是CFTR受损的直接影响 疾病进展的功能或继发性表现目前尚不清楚。同样不清楚的是 调理治疗在逆转这些表型方面的疗效。我们最近做了 已发表的一项研究表明，在CF小鼠模型中，CR基因的表达发生了变化，表明CR 调节失调是CF的主要表现。从机制上讲，我们之前已经报道过 纤维细胞微管调节的改变。这些发现导致了一种假设，即 由于微管不稳定和随后的褪黑素减少，CF的调节发生了变化 制作。微管被认为在CR中扮演着重要的角色，我们已经 先前研究表明，CF细胞的乙酰化程度降低，微管速度减慢 形成率。我们最近还发表了微管调节的耗竭 小鼠的蛋白质(微管蛋白聚合促进蛋白，TPPP)复制CF样CR 支持微管在CF表型中的作用的破坏。初步数据显示 CF小鼠产生的褪黑素水平降低，褪黑素是一种关键的CR调节因子，也是已知的 微管稳定性。这些数据表明褪黑素和/或微管靶向化合物 可能的治疗干预措施，可以加强调节剂治疗或允许另一种选择 解决慢性粒细胞白血病患者CR相关表型的方法。该研究的目标是 确定cftr在CR调节中的作用以及cftr校正是否影响cr基因 表达和相关的行为结果。我们还将努力了解细胞 这些调控关系中涉及的机制可以作为治疗靶点。至 为实现这些目标，将研究以下具体目标：目标1.确定CFTR值-- CR调节的依赖性和高效CFTR调节剂逆转效应的研究 Cf相关CR表型。目的2.明确慢性萎缩性胃炎患者CR功能失调的机制。目标3. CFTR调节剂对昼夜节律的影响及褪黑素的测定 患有儿童和青少年的儿童和青少年的生产。

Although in cystic fibrosis (CF) patients, respiratory and digestive disease is the primary source of morbidity and mortality there are many other clinically relevant symptoms such as depression and anxiety, and poor sleep quality, including sleep disturbances, and altered sleep patterns. Sleep disturbances experienced by individuals with CF are consistent with circadian rhythm (CR) phase delays. The clinical relevance of CR and sleep regulation in CF can be seen in studies that demonstrate CF patients with poor sleep quality have more severe lung disease and poorer outcomes over time. Whether CR disruption in CF is a direct effect of impaired CFTR function or a secondary manifestation of disease progression is currently unclear. Also unclear is the efficacy of modulatory therapy in CF in reversing these phenotypes. We have recently published that CR gene expression is altered in a CF mouse model suggesting that CR dysregulation is a primary manifestation of CF. Mechanistically, we have previously reported alterations in microtubule regulation in CF cells. These findings lead to the hypothesis that CR regulation in CF is altered due microtubule instability and consequent reductions in melatonin production. Microtubules have been suggested to play an important role in CR, and we have previously demonstrated that CF cells display reduced acetylation and slower microtubule formation rates. We have also recently published that depletion of a microtubule modulating protein (tubulin polymerization promoting protein, TPPP) from mice replicates CF-like CR disruptions that support a role of microtubules in CF phenotypes. Preliminary data demonstrate that CF mice produce reduced levels of melatonin, a key CR regulator and known regulator of microtubule stability. These data suggest melatonin and/or microtubule targeted compounds as possible therapeutic interventions that can augment modulator therapy or allow an alternative approach to address CR-related phenotypes in CF patients. The goals of the study are to determine the role of CFTR in CR regulation and if CFTR correction influences CR gene expression and related behavioral outcomes. We also will strive to understand the cellular mechanisms involved in these regulatory relationships that can be therapeutically targeted. To achieve these goals, the following specific aims will be studied: Aim 1. To determine the CFTR- dependency of CR regulation and the efficacy of highly-effective CFTR modulators in reversing CF-related CR phenotypes. Aim 2. To identify mechanisms of CR dysregulation in CF. Aim 3. To determine the effect of CFTR modulators on circadian rhythm and to determine melatonin production in children and adolescents with CF.