The body?s internal clock (i.e., circadian rhythm) controls the timing of many aspects of physiology, metabolism, and behavior. Disruption of circadian rhythms has been implicated in a surprisingly large number of diseases, including many types of depression, autism, several types of cancer, and several neurodegenerative disorders, and mounting evidence suggests that treatment for these diseases timed optimally with respect to the body?s internal clock is critical to their effectiveness. There are two primary barriers to implementing such ?circadian-based? interventions in clinical practice, however. First, the timing of the internal clock can vary by 5 to 8 hours in healthy individuals (even more variable in patient populations). Thus, although many drugs are given based on time of day, e.g., morning vs. evening administration, a drug administered at 8am in one individual may be administered at the biologically equivalent time of 3am in another individual. Second, internal clock time is difficult to assess in a non-research setting. Current gold-standard methods require serial measurement of a single compound that exhibits a robust circadian rhythm (e.g., melatonin) over a 24- to 48-hour sampling window, which is invasive, time-consuming and costly. Instead of measuring one compound in serial samples, an alternate approach for assessing internal clock time is to measure multiple compounds from a single sample. Recently, several groups have reported the ability to assess internal clock time from multiple metabolite or transcriptomics rhythms measured from one or two blood samples. While these methods represent a major advance in the ability to estimate internal clock time, blood sampling remains invasive and the internal clock time derived from these methods is accurate only under limited conditions. Here, we propose a metabolomics approach to assess internal clock time from a single urine void. Our recent pilot analysis in n=3 participants has identified several candidate compounds from over 4,000 annotated metabolites detected by untargeted urine metabolomics profiling. The goal of this current proposal is to confirm these candidate compounds in a larger sample size and test the ability of these compounds to accurately assess internal clock time to within 30 minutes against a gold-standard measure. The ability to assess internal clock time in a non-invasive and time- and cost-effective manner has direct
Metabolomic approaches will be utilized to enable accurate measurement of internal clock time from a single urine void. Because many therapeutic interventions are more effective when administered at certain times with respect to the internal clock, the findings from this proposal are expected to improve precision medicine across a wide range of diseases.
