Real-time breath metabolomics: A new direction for circadian biomarkers

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ABSTRACT The goal of the project is to optimize human health, performance, and safety by developing robust diagnostic biomarkers for circadian timing to identify, from a single biospecimen, the biological time within an individual. Our understanding of the importance of circadian timing to human health is increasing; disruption of circadian timing is associated with metabolic disorders, cardiovascular disease, immune dysregulation, and cancers. A recent study tested ~17,000 genes and found that nearly half cycled in at least one human tissue, and more than 900 of those cycling genes coded for proteins that are drug targets, transport drugs, or are involved in drug metabolism. Building on this emerging knowledge, we should be able to regularize circadian timing to prevent disease, and to administer many short half-life drugs at their ideal circadian time to increase efficacy and/or reduce side effects. However, our ability to incorporate circadian timing into clinical decision-making and treatment is impaired by our current inability to measure circadian phase quickly and easily. Current methods for assessing circadian timing require sampling over hours (or even up to a day) while the patient is in controlled conditions. In the parent grant we aim to develop methods that can estimate individual circadian time with a single blood sample taken at any time of the day or night using a plasma proteomics-based method to identify a panel of rhythmic proteins, as well as refining a monocyte-based method using a panel of 15 transcripts. In this New Research Direction project, we will expand our circadian biomarker efforts to include development of a breath biomarker for circadian timing. We will use real-time breath metabolomics technology called selected-ion flow-tube mass spectrometry (SIFT-MS) to search for breath biomarkers of circadian time. We will add collection of breath samples every 3 hours to the studies in the parent grant, using the rigorous constant routine methodology in highly controlled laboratory conditions to ensure any observed oscillations in breath metabolites are due to endogenous variations in breath components rather than representing responses to changes in activity, food/fluid intake or composition, or sleep-wake state. We will validate the breath metabolomics biomarker against circadian phase estimate derived from plasma melatonin (the current “gold-standard” phase marker). When fully developed, this breath-based method will enable on-demand monitoring of circadian status non-invasively and in real-time. The proposed New Research Direction project has the potential to develop a rapid, real-time, non-invasive method for diagnosis and treatment of patients with suspected circadian rhythm disorders (delayed sleep-wake phase disorder, shift work disorder) and other sleep pathologies (insomnia, hypersomnia) and to advance the potential of personalized medicine through individualized treatment timing (chronomedicine). -1-