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: 10610462
• 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/10610462
• 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; Growth; Human; Impairment; Inbred CFTR Mice; Knock-out; Knockout Mice; Lead; Link; Lung diseases; Melatonin; Mental Depression; Microtubule Alteration; Microtubules; Morbidity - disease rate; Mus; Outcome; Pathway interactions; Patients; Pattern; Phase; Phenotype; Play; Polymers; 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，呼吸系统和消化系统疾病是主要的 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，以及睡眠质量差，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 心律 (CR) 相位延迟。可见 CR 和 CF 睡眠调节的临床相关性 研究表明睡眠质量差的 CF 患者患有更严重的肺部疾病 随着时间的推移，结果会变得更差。 CF 中的 CR 破坏是否是 CFTR 受损的直接影响 目前尚不清楚其功能或疾病进展的继发表现。还不清楚的是 CF 调节疗法在逆转这些表型方面的功效。我们最近有 发表了 CR 基因表达在 CF 小鼠模型中发生改变，表明 CR 调节失调是 CF 的主要表现。从机制上讲，我们之前报道过 CF细胞中微管调节的改变。这些发现导致了这样的假设：CR 由于微管不稳定和随之而来的褪黑激素减少，CF 的调节发生改变 生产。微管已被认为在 CR 中发挥重要作用，我们已经 先前证明 CF 细胞表现出乙酰化程度降低和微管速度减慢 形成率。我们最近还发表了微管调节的耗尽 来自小鼠的蛋白质（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。初步数据表明 CF 小鼠产生的褪黑激素水平降低，褪黑激素是关键的 CR 调节剂，也是已知的 CR 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 可能的治疗干预措施可以增强调节剂治疗或允许替代疗法 解决 CF 患者 CR 相关表型的方法。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。我们还将努力了解细胞 涉及这些调节关系的机制可以作为治疗目标。到 为了实现这些目标，将研究以下具体目标： 目标 1. 确定 CFTR- CR调节的依赖性和高效CFTR调节剂在逆转中的功效 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 患有 CF 的儿童和青少年的生产。