Altered Circadian Rhythm Regulation in Cystic Fibrosis

囊性纤维化的昼夜节律调节发生改变

• 批准号: 10442072
• 负责人: Rebecca J Darrah
• 金额: $ 62.62万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442072
• 关键词: Acetylation; Address; Adolescent; Adolescent and Young Adult; Age; Anxiety; Automobile Driving; Biogenesis; Biological Process; Cells; Child; Circadian Dysregulation; Circadian Rhythms; Clinical Data; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Delta F508 mutation; Dependence; Digestive System Disorders; Disease; Disease Progression; Eligibility Determination; Exhibits; Functional disorder; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Generations; Genotype; Goals; Human; Impairment; Inbred CFTR Mice; Knock-out; Lead; Link; Lung diseases; Melatonin; Mental Depression; Microtubule Alteration; Microtubules; Morbidity - disease rate; Mouse Protein; Mus; Outcome; Pathway interactions; Patients; Pattern; Phase; Phenotype; Play; Process; Production; Proteins; Publishing; Regulation; Reporting; Respiratory Disease; Role; Sleep; Sleep disturbances; Source; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Tryptophan Metabolism Pathway; Tubulin; actigraphy; behavioral outcome; children with cystic fibrosis; circadian; clinical development; clinically relevant; cystic fibrosis mouse; cystic fibrosis patients; efficacy evaluation; efficacy testing; experience; healthy volunteer; insight; mortality; mouse model; pediatric patients; polymerization; poor sleep; sleep pattern; sleep quality; sleep regulation; therapeutic development; therapeutic target; therapy development; young adult

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.

尽管在囊性纤维化（CF）患者中，呼吸道和消化疾病是主要的 发病率和死亡率的来源还有许多其他临床相关症状，例如 抑郁和焦虑以及睡眠质量不佳，包括睡眠障碍和睡眠改变 模式。 CF患者经历的睡眠障碍与昼夜节律一致 节奏（CR）阶段延迟。可以看到CF和睡眠调节的临床相关性 在表明睡眠质量较差的CF患者的研究中患有更严重的肺部疾病 随着时间的流逝，结果较差。 CF中的CR中断是否是CFTR受损的直接影响 目前尚不清楚疾病进展的功能或次要表现。也不清楚 调节疗法在CF逆转这些表型中的功效。我们最近有 发表的CF基因表达在CF小鼠模型中发生了改变，表明CR 失调是CF的主要表现。从机械上讲，我们以前报道了 CF细胞中微管调控的改变。这些发现导致了CR的假设 由于微管的不稳定性而改变了CF的调节，因此褪黑激素的减少 生产。已经建议微管在CR中发挥重要作用，我们有 以前证明CF细胞显示乙酰化降低和较慢的微管 形成率。我们最近还发布了微管调节的耗竭 小鼠的蛋白质（促进蛋白质的微管蛋白聚合促进蛋白）复制CF样CR 支持微管在CF表型中的作用的破坏。初步数据证明了 CF小鼠产生的褪黑激素水平降低，褪黑激素是一个关键的CR调节剂和已知调节剂 微管稳定性。这些数据表明褪黑激素和/或微管靶向化合物作为 可能会增加调节剂疗法或允许替代的治疗干预措施 解决CF患者中与CR相关的表型的方法。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。我们还将努力理解细胞 这些法规关系涉及的机制可以针对治疗。到 实现这些目标，将研究以下特定目标：目标1。确定CFTR- CR调节的依赖性以及高效CFTR调制器逆转的功效 CF相关的CR表型。目标2。确定CF中CR失调的机制。目标3。 确定CFTR调节剂对昼夜节律的影响并确定褪黑激素 CF的儿童和青少年生产。