Abstract
Cystic fibrosis (CF) is autosomal recessive disease that affects multiple body systems. CF patients often experience sleep disturbances, altered sleep patterns, and sleep apnea. Sleep in mammals is controlled in part by circadian clock genes, including Clock, Bmal1, Period1, Period2, Cryptochrome1, and Cryptochrome2. The purpose of this study was to gain a better understanding of the biological underpinnings of disordered sleep experienced in CF. To accomplish this, we evaluated circadian clock gene expression profiles in CF and wildtype mice, divided into two subgroups each based on sleep condition. One subgroup of each genotype was permitted to maintain their sleep-wake cycle while the other was deprived of sleep for six hours prior to sacrifice. Brain, skeletal muscle, jejunum, colon, lung and adipose tissues were collected from each mouse. Quantitative polymerase chain reaction (PCR) was used to quantify expression of Clock, Bmal1, Period1, Period2, Cryptochrome1 and Cryptochrome2, and expression levels were compared between study groups. Our comparisons showed distinct differences between the CF groups and the wildtype groups under both sleep conditions. Additionally, we found the CF mice that had been sleep deprived had severely dysregulated expression of all measured genes in the lung apart from Cry1. Our findings suggest that (1) disordered sleep in CF may be caused by circadian system dysregulation and (2) the loss of the cystic fibrosis transmembrane conductance regulator (CFTR) is a causative factor in the dysregulated circadian clock gene expression profiles of CF mice.
Highlights
Cystic Fibrosis (CF), an autosomal recessive disease that affects approximately 1 in 2,500 Caucasian newborns, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
Because of the nocturnal nature of mice and the fluctuation of circadian clock gene expression throughout the 24-hour cycle, the above protocols were completed during the day and all mice were sacrificed at the same time [15, 17, 21]
Group comparison 1: WT rested vs. CF rested To determine whether the circadian clock gene expression profiles of CF mice differ from those of WT mice at baseline, we compared gene expression data from our
Summary
Cystic Fibrosis (CF), an autosomal recessive disease that affects approximately 1 in 2,500 Caucasian newborns, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Though the disease affects nearly every body system, the respiratory and digestive systems are the primary sources of morbidity and mortality in CF [1]. Due to their disproportionately high contribution to complications in CF, these systems are often the most heavily studied. CF patients, experience many other clinically relevant symptoms such as poor sleep quality [2, 3]. Of particular concern to CF patients, poor sleep quality has been associated with impaired immune response and increased susceptibility to infectious diseases [8]. Cognitive performance has been shown to decline with consecutive hours of sleep deprivation, in relation to complex task performance such as decision making, multitasking, memory tasks, and team performance tasks [10]
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