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.

虽然在囊性纤维化（CF）患者中，呼吸和消化系统疾病是主要的