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Molecular Insights and Multi-Omics in Sleep Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 22716

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Special Issue Editors

Prof. Dr. David Gozal

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Guest Editor

Department of Child Health and the Child Health Research Institute, University of Missouri School of Medicine, Columbia, MO 65201, USA
Interests: sleep; sleep disorders; hypoxia; pediatric respiratory diseases; cardiorespiratory physiology

Prof. Dr. Sina A. Gharib

E-Mail Website
Guest Editor

Computational Medicinal Core, Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, S376-815 Mercer, Box 385052, Seattle, WA 98109, USA
Interests: matrix metalloproteinase; pulmonary; lung biology

Dr. Rene Cortese

E-Mail Website
Guest Editor

School of Medicine, University of Missouri, Columbia, MO 65211, USA
Interests: epigenomics; sleep disorders; multiomics; obstructive sleep apnea; developmental origin of diseases; circulating DNA; liquid biopsies; cognitive disorders; cardiometabolic disorders; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sleep disorders are very common conditions affecting billions of people around the world throughout their lifespans that manifest as heterogeneous phenotypes across gender and ethnic backgrounds. When the quality and/or amount of sleep is affected, adverse consequences occur with both short-term and long-term implications. Examples of highly prevalent sleep disorders include, among others, sleep disordered breathing (e.g., obstructive and central sleep apnea syndromes), insomnia, hypersomnia, circadian rhythm disorders, and parasomnias. Sleep disorders result in numerous morbidities, including metabolic, cardiovascular, cognitive, behavioral and mood perturbations, which can further exacerbate the adverse outcomes and result in increased mortality.

Considering that sleep serves as a life-sustaining function and that it also embodies one of the pillars of health and wellness, it should not be surprising that a great deal of pathophysiological processes affecting virtually every system in the body may in turn affect sleep quality and quantity. Conversely, the presence of sleep disorders will entail an increased risk for the emergence of associated morbidities. As such, unraveling the cellular and molecular mechanisms that are dysregulated in the sleep-function dyad of interest is paramount to understand the causes and consequences of sleep disorders and to develop diagnostic and therapeutic approaches, particularly in the era of precision medicine. Over the last three decades, there has been a continuous growth of research studies applying advanced techniques towards this goal. The application of highly sensitive molecular techniques, such as qPCR, flow cytometry, and spectrometry, have provided high resolution mapping of molecular mechanisms and biochemical pathways affected by sleep and circadian processes, and have also uncovered similar processes related to specific sleep disorders and their associated morbidities. Furthermore, the development of large-scale high-throughput methodologies has enabled the parallel analysis of thousands of variations at genomic, transcriptomic, proteomic, epigenomic, microbiomic, and metabolomic levels. The development and application of such “omic” technologies have opened the way for a new and burgeoning field in sleep-related research and has generated large amounts of data while uncovering exciting and novel insights into the etiology of sleep disorders. Notwithstanding, these different molecular layers interact in a complex and organized manner and such a large number of data need to be consolidated and interpreted together to provide the most comprehensive picture of the mechanisms being recruited and involved in both normal and disease states as related to sleep and circadian rhythms. The integration of such large and complex datasets requires the application of advanced bioinformatic approaches, many of which are being developed.

This Special Issue is dedicated to highlighting the most recent advances in molecular research on sleep disorders, from studies focused on single molecules and pathways to large, integrative, multi-omic analyses. As such, we invite the submission of manuscripts encompassing any studies that are focused on sleep and circadian biology that employ omic or molecular approaches to increase our understanding of perturbations in sleep and biological clocks and the mechanism implicated in the attendant consequences of such perturbations.

Prof. Dr. David Gozal
Prof. Dr. Sina A. Gharib
Dr. Rene Cortese
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

sleep disorders
sleep
circadian
genome
proteome
metabolome
transcriptome
epigenome
microbiome
molecular diagnostics
pharmacogenomics
precision medicine
bioinformatics methods
cellular models
animal models
narcolepsy
sleep apnea
sleep-disordered breathing
insomnia
periodic leg movement disorder of sleep
obstructive sleep apnea
central sleep apnea
obesity hypoventilation syndrome

Published Papers (7 papers)

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Research

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16 pages, 3606 KiB

Open AccessArticle

Chronic Intermittent Hypoxia during Sleep Causes Browning of Interscapular Adipose Tissue Accompanied by Local Insulin Resistance in Mice

by Tehila Dahan, Shahd Nassar, Olga Yajuk, Eliana Steinberg, Ofra Benny, Nathalie Abudi, Inbar Plaschkes, Hadar Benyamini, David Gozal, Rinat Abramovitch and Alex Gileles-Hillel

Int. J. Mol. Sci. 2022, 23(24), 15462; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415462 - 07 Dec 2022

Cited by 6 | Viewed by 3073

Abstract

Obstructive sleep apnea (OSA) is a highly prevalent condition, characterized by intermittent hypoxia (IH), sleep disruption, and altered autonomic nervous system function. OSA has been independently associated with dyslipidemia, insulin resistance, and metabolic syndrome. Brown adipose tissue (BAT) has been suggested as a modulator of systemic glucose tolerance through adaptive thermogenesis. Reductions in BAT mass have been associated with obesity and metabolic syndrome. No studies have systematically characterized the effects of chronic IH on BAT. Thus, we aimed to delineate IH effects on BAT and concomitant metabolic changes. C57BL/6J 8-week-old male mice were randomly assigned to IH during sleep (alternating 90 s cycles of 6.5% F_IO₂ followed by 21% F_IO₂) or normoxia (room air, RA) for 10 weeks. Mice were subjected to glucose tolerance testing and ¹⁸F-FDG PET–MRI towards the end of the exposures followed by BAT tissues analyses for morphological and global transcriptomic changes. Animals exposed to IH were glucose intolerant despite lower total body weight and adiposity. BAT tissues in IH-exposed mice demonstrated characteristic changes associated with “browning”—smaller lipids, increased vascularity, and a trend towards higher protein levels of UCP1. Conversely, mitochondrial DNA content and protein levels of respiratory chain complex III were reduced. Pro-inflammatory macrophages were more abundant in IH-exposed BAT. Transcriptomic analysis revealed increases in fatty acid oxidation and oxidative stress pathways in IH-exposed BAT, along with a reduction in pathways related to myogenesis, hypoxia, and IL-4 anti-inflammatory response. Functionally, IH-exposed BAT demonstrated reduced absorption of glucose on PET scans and reduced phosphorylation of AKT in response to insulin. Current studies provide initial evidence for the presence of a maladaptive response of interscapular BAT in response to chronic IH mimicking OSA, resulting in a paradoxical divergence, namely, BAT browning but tissue-specific and systemic insulin resistance. We postulate that oxidative stress, mitochondrial dysfunction, and inflammation may underlie these dichotomous outcomes in BAT. Full article

(This article belongs to the Special Issue Molecular Insights and Multi-Omics in Sleep Disorders)

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18 pages, 4545 KiB

Open AccessArticle

Caffeine-Induced Sleep Restriction Alters the Gut Microbiome and Fecal Metabolic Profiles in Mice

by Zan Song, Lin Liu, Yanyi Xu, Ruofan Cao, Xianyong Lan, Chuanying Pan, Shengxiang Zhang and Haiyu Zhao

Int. J. Mol. Sci. 2022, 23(23), 14837; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314837 - 27 Nov 2022

Cited by 5 | Viewed by 2373

Abstract

Insufficient sleep is becoming increasingly common and contributes to many health issues. To combat sleepiness, caffeine is consumed daily worldwide. Thus, caffeine consumption and sleep restriction often occur in succession. The gut microbiome can be rapidly affected by either one’s sleep status or caffeine intake, whereas the synergistic effects of a persistent caffeine-induced sleep restriction remain unclear. In this study, we investigated the impact of a chronic caffeine-induced sleep restriction on the gut microbiome and its metabolic profiles in mice. Our results revealed that the proportion of Firmicutes and Bacteroidetes was not altered, while the abundance of Proteobacteria and Actinobacteria was significantly decreased. In addition, the content of the lipids was abundant and significantly increased. A pathway analysis of the differential metabolites suggested that numerous metabolic pathways were affected, and the glycerophospholipid metabolism was most significantly altered. Combined analysis revealed that the metabolism was significantly affected by variations in the abundance and function of the intestinal microorganisms and was closely relevant to Proteobacteria and Actinobacteria. In conclusion, a long-term caffeine-induced sleep restriction affected the diversity and composition of the intestinal microbiota in mice, and substantially altered the metabolic profiles of the gut microbiome. This may represent a novel mechanism by which an unhealthy lifestyle such as mistimed coffee breaks lead to or exacerbates disease. Full article

(This article belongs to the Special Issue Molecular Insights and Multi-Omics in Sleep Disorders)

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19 pages, 1009 KiB

Open AccessArticle

Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response

by Katie L. J. Cederberg, Umaer Hanif, Vicente Peris Sempere, Julien Hédou, Eileen B. Leary, Logan D. Schneider, Ling Lin, Jing Zhang, Anne M. Morse, Adam Blackman, Paula K. Schweitzer, Suresh Kotagal, Richard Bogan, Clete A. Kushida, Yo-El S. Ju, Nayia Petousi, Chris D. Turnbull, Emmanuel Mignot and The STAGES Cohort Investigator Group

Int. J. Mol. Sci. 2022, 23(14), 7983; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147983 - 20 Jul 2022

Cited by 8 | Viewed by 3843

Abstract

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea–hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke. Full article

(This article belongs to the Special Issue Molecular Insights and Multi-Omics in Sleep Disorders)

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Review

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24 pages, 3892 KiB

Open AccessReview

Experimental Models to Study End-Organ Morbidity in Sleep Apnea: Lessons Learned and Future Directions

by Ramon Farré, Isaac Almendros, Miguel-Ángel Martínez-García and David Gozal

Int. J. Mol. Sci. 2022, 23(22), 14430; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214430 - 20 Nov 2022

Cited by 7 | Viewed by 2045

Abstract

Sleep apnea (SA) is a very prevalent sleep breathing disorder mainly characterized by intermittent hypoxemia and sleep fragmentation, with ensuing systemic inflammation, oxidative stress, and immune deregulation. These perturbations promote the risk of end-organ morbidity, such that SA patients are at increased risk of cardiovascular, neurocognitive, metabolic and malignant disorders. Investigating the potential mechanisms underlying SA-induced end-organ dysfunction requires the use of comprehensive experimental models at the cell, animal and human levels. This review is primarily focused on the experimental models employed to date in the study of the consequences of SA and tackles 3 different approaches. First, cell culture systems whereby controlled patterns of intermittent hypoxia cycling fast enough to mimic the rates of episodic hypoxemia experienced by patients with SA. Second, animal models consisting of implementing realistic upper airway obstruction patterns, intermittent hypoxia, or sleep fragmentation such as to reproduce the noxious events characterizing SA. Finally, human SA models, which consist either in subjecting healthy volunteers to intermittent hypoxia or sleep fragmentation, or alternatively applying oxygen supplementation or temporary nasal pressure therapy withdrawal to SA patients. The advantages, limitations, and potential improvements of these models along with some of their pertinent findings are reviewed. Full article

(This article belongs to the Special Issue Molecular Insights and Multi-Omics in Sleep Disorders)

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14 pages, 845 KiB

Open AccessReview

How Temperature Influences Sleep

by Yaqian Fan, Yuedong Wang, Pengyu Gu, Junhai Han and Yao Tian

Int. J. Mol. Sci. 2022, 23(20), 12191; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012191 - 13 Oct 2022

Cited by 4 | Viewed by 3631

Abstract

Sleep is a fundamental, evolutionarily conserved, plastic behavior that is regulated by circadian and homeostatic mechanisms as well as genetic factors and environmental factors, such as light, humidity, and temperature. Among environmental cues, temperature plays an important role in the regulation of sleep. This review presents an overview of thermoreception in animals and the neural circuits that link this process to sleep. Understanding the influence of temperature on sleep can provide insight into basic physiologic processes that are required for survival and guide strategies to manage sleep disorders. Full article

(This article belongs to the Special Issue Molecular Insights and Multi-Omics in Sleep Disorders)

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22 pages, 1861 KiB

Open AccessReview

The Role of Inflammation, Hypoxia, and Opioid Receptor Expression in Pain Modulation in Patients Suffering from Obstructive Sleep Apnea

by Piotr Kaczmarski, Filip Franciszek Karuga, Bartosz Szmyd, Marcin Sochal, Piotr Białasiewicz, Dominik Strzelecki and Agata Gabryelska

Int. J. Mol. Sci. 2022, 23(16), 9080; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169080 - 13 Aug 2022

Cited by 20 | Viewed by 2834

Abstract

Obstructive sleep apnea (OSA) is a relatively common disease in the general population. Besides its interaction with many comorbidities, it can also interact with potentially painful conditions and modulate its course. The association between OSA and pain modulation has recently been a topic of concern for many scientists. The mechanism underlying OSA-related pain connection has been linked with different pathophysiological changes in OSA and various pain mechanisms. Furthermore, it may cause both chronic and acute pain aggravation as well as potentially influencing the antinociceptive mechanism. Characteristic changes in OSA such as nocturnal hypoxemia, sleep fragmentation, and systemic inflammation are considered to have a curtailing impact on pain perception. Hypoxemia in OSA has been proven to have a significant impact on increased expression of proinflammatory cytokines influencing the hyperalgesic priming of nociceptors. Moreover, hypoxia markers by themselves are hypothesized to modulate intracellular signal transduction in neurons and have an impact on nociceptive sensitization. Pain management in patients with OSA may create problems arousing from alterations in neuropeptide systems and overexpression of opioid receptors in hypoxia conditions, leading to intensification of side effects, e.g., respiratory depression and increased opioid sensitivity for analgesic effects. In this paper, we summarize the current knowledge regarding pain and pain treatment in OSA with a focus on molecular mechanisms leading to nociceptive modulation. Full article

(This article belongs to the Special Issue Molecular Insights and Multi-Omics in Sleep Disorders)

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23 pages, 1782 KiB

Open AccessReview

PAI-1: A Major Player in the Vascular Dysfunction in Obstructive Sleep Apnea?

by Mohammad Badran and David Gozal

Int. J. Mol. Sci. 2022, 23(10), 5516; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105516 - 15 May 2022

Cited by 10 | Viewed by 3824

Abstract

Obstructive sleep apnea is a chronic and prevalent condition that is associated with endothelial dysfunction, atherosclerosis, and imposes excess overall cardiovascular risk and mortality. Despite its high prevalence and the susceptibility of CVD patients to OSA-mediated stressors, OSA is still under-recognized and untreated in cardiovascular practice. Moreover, conventional OSA treatments have yielded either controversial or disappointing results in terms of protection against CVD, prompting the need for the identification of additional mechanisms and associated adjuvant therapies. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-type plasminogen activator (tPA) and urinary-type plasminogen activator (uPA), is a key regulator of fibrinolysis and cell migration. Indeed, elevated PAI-1 expression is associated with major cardiovascular adverse events that have been attributed to its antifibrinolytic activity. However, extensive evidence indicates that PAI-1 can induce endothelial dysfunction and atherosclerosis through complex interactions within the vasculature in an antifibrinolytic-independent matter. Elevated PAI-1 levels have been reported in OSA patients. However, the impact of PAI-1 on OSA-induced CVD has not been addressed to date. Here, we provide a comprehensive review on the mechanisms by which OSA and its most detrimental perturbation, intermittent hypoxia (IH), can enhance the transcription of PAI-1. We also propose causal pathways by which PAI-1 can promote atherosclerosis in OSA, thereby identifying PAI-1 as a potential therapeutic target in OSA-induced CVD. Full article

(This article belongs to the Special Issue Molecular Insights and Multi-Omics in Sleep Disorders)

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