CE14 - Physiologie et physiopathologie

Interaction between hypoxia and the circadian clock in the development of sleep apnea-rmediated liver disease – TEMPORISE

Interaction between hypoxia and the biological clock in the development of liver disease associated with sleep apnea syndrome

Sleep apnea syndrome (SAS) is one of the most common chronic diseases affecting nearly one billion people worldwide. The existence and degree of severity of SAS influences the severity of other diseases and promotes the development of hypertension, diabetes, liver disease, arrhythmias, and coronary heart disease.

The development of liver disease in sleep apnea syndrome could be the result of deregulation of epigenetic changes and circadian rhythms.

Sleep apnea syndrome (SAS) is characterized by repeated upper airway collapse during sleep generating cycles of desaturation-reoxygenation leading to intermittent hypoxia (IH). Several recent studies have shown interconnections between hypoxia, circadian rhythms and epigenetics modifications. However, little data exists on these interactions during SAS when intermittent hypoxia occurs circadian (during sleep). The objective of this project is to demonstrate that the reprogramming of epigenetic changes and circadian homeostasis by intermittent hypoxia contributes to the organ damage observed in SAS with a first demonstrator for liver disease. First, we aim to explore the kinetics of the course of hepatic injury during exposure to intermittent hypoxia and to characterize the timing of disruption of circadian rhythms due to intermittent hypoxia. Next, we want to understand the molecular mechanisms involved in this deregulation, by studying the interactions between the circadian clock and the response to hypoxia in the regulation of gene expression. Finally, we will analyze the effects of circadian clock disruption and hypoxia response on the development of HI-induced liver damage using appropriate knockout mouse models.

Phenotypic characterization will be done through histological, hematological (blood tests) and telemetry (implants and behavioral phenotyping platforms) strategies. Molecular approaches such as transcriptomics, epigenomics and proteomics will allow us to discover the molecular signatures associated with intermittent hypoxia.

Confidential

Currently, no biomarkers are described in sleep apnea syndrome and the molecular mechanisms associated with intermittent hypoxia are poorly detailed. This lack of data is a major problem in the implementation of personalized medicine. We hope that this project will allow the identification of molecular signatures which can then be confirmed in apneic patients. This project will also pave the way for new therapeutic targets and behavioral interventions. Finally, the scientific strategy deployed for liver damage could be duplicated for other organs affected by sleep apnea syndrome.

Ongoing

Obstructive Sleep Apnea (OSA) is one of the most frequent chronic disease affecting nearly one billion people worldwide. OSA corresponds to the repetitive occurrence of complete (apneas) and incomplete (hypopneas) pharyngeal collapses during sleep leading to cycling hypoxia-re-oxygenation sequences called intermittent hypoxia. OSA is a growing health concern, highlighted by a societal and economic burden close to hypertension or stroke. OSA is associated and modulate severity of various chronic diseases including metabolic syndrome, nonalcoholic fatty liver diseases and cardiovascular disease. The landmark feature of OSA is a chronic intermittent hypoxia (CIH) associated with apneas/hypopneas leading to activation of the hypoxia-inducible transcription factors (HIF) directly responsible for multiple organ damages including liver disease. The interconnections between hypoxia and circadian rhythms has become a hot research topic in physiological science. This link is largely explained by transcriptional and epigenetic mechanisms. However, data are limited regarding these interactions in OSA, a particularly relevant disease since it induces intermittent hypoxia during a specific circadian time period (sleep). This is therefore an important emerging area to explore and the main goal of this project is to demonstrate that reprogramming of circadian homeostasis by CIH is a key mechanism underlying OSA-related organ injury with a specific focus on liver disease. Given the intimate link between hypoxia, circadian rhythms and chromatin dynamics, by understanding how these components act as a coordinated network TEMPORISE may provide novel insight into how these factors contribute to liver disease in general and more specifically in OSA. First, we aim to explore the kinetics of liver disease evolution under intermittent hypoxia exposure and to characterize the timing of circadian rhythm perturbation by CIH. Second, we wish to understand molecular mechanisms underlying circadian clock dysregulation at the onset of liver disease, through a molecular study of the interaction between the circadian clock and HIF-1 and the associated transcriptional and epigenetics consequences. Third, we want to analyze the effect of circadian clock and HIF-1 disruption on CIH-induced liver disease development through histological characterization and the use of appropriate knockout mouse models. The combined expertise of the coordinator and the partners are major assets for the TEMPORISE project. This project will take advantage of state-of-the art technics such as epigenomics, transcriptomics, proteomics and bioinformatics approaches. Altogether, we expect that unraveling novel mechanisms interconnecting CIH and circadian clock defects will provide new insight in the understanding of liver diseases development and pave new avenues towards pharmacological interventions.

Project coordination

Jean-Louis PEPIN (HYPOXIE : PHYSIOPATHOLOGIE CARDIOVASCULAIRE ET RESPIRATOIRE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

BGE BIOLOGIE A GRANDE ECHELLE
IAB Institut pour l'Avancée des Biosciences
HP2 HYPOXIE : PHYSIOPATHOLOGIE CARDIOVASCULAIRE ET RESPIRATOIRE

Help of the ANR 356,729 euros
Beginning and duration of the scientific project: December 2019 - 36 Months

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