Subproject for Biochronicity Grand Challenge: Human Time Stamp Development, Validation and Prediction

Our genomes are temporally organized by circadian clocks with respect to our 24 h environment. Circadian clocks are not only found in discrete areas of the brain but are found in virtually every organ in our bodies. Disruptions in circadian clocks, or chronopathology, may underlie various forms of neurological, cardiovascular, and metabolic disease. Over the past two decades, there has been a revolution in our understanding of the molecular basis of circadian clock function. In fact, these discoveries have been cited three times among Science magazine’s Breakthroughs of the Year. These molecular insights afford us an unprecedented opportunity to investigate the prevalence of circadian disruption at the molecular level in a wide range of patient populations. Indeed, it is difficult to find a specific molecular network with such a broad influence in human disease. Here we propose to analyze the transcriptome across 24 h from human blood. Analysis of blood markers not only reflect the state of clocks in blood immune cells but can also indirectly reveal the temporal organization of organ systems including the brain. We will computationally analyze these genomic snapshots to identify biomarker signatures, we term Time Stamps, that enable us to tell endogenous biological time and its underlying organization from just a single or a few blood draws. We will then determine if these Time Stamps can predict clinical outcomes in those with traumatic brain injuries (TBI). To determine the predictive value of Time Stamps, we will examine them in control healthy individuals with a normal chronotype (i.e., typical sleep and wake schedule) and then individuals with traumatic brain injury (with and without evidence of abnormal chronotype). In concert with the Northwestern Center for Circadian and Sleep Medicine, recruited healthy subjects will be kept under tightly controlled “constant routine” conditions (dim light, evenly spaced meals) to enable isolation of the role of internal biological clocks. We will determine if Time Stamps derived from these lab measures predict biological time in outpatients and if Time Stamps are reproducible across populations. The CCSM clinical research infrastructure is a unique resource that will enable high temporal resolution analyses in a restricted timeframe. To test the initial clinical value of Time Stamps for characterizing and predicting clinical outcomes, we will collaborate with Rehabilitation Institute of Chicago (RIC). RIC is a premier institution for the treatment and study of TBI. TBI has been called the signature battlefield injury of the recent conflicts in Iraq and Afghanistan and impacts over a million people in the U.S each year off the battlefield. There is evidence that those with TBI exhibit evidence of clock disruption. As part of our current Biochronicity program, we have also demonstrated that clock disruption can modulate neuronal viability in neurodegenerative diseases. We hypothesize that clock disruption in the context of TBI could therefore predict disease course. We will collect samples as outpatients with those with TBI. To determine if clock algorithms are predictive in various conditions, such algorithms can be diagnostic, i.e., differentiate healthy and disease, and/or prognostic, i.e., predict future disease course. Time Stamp analysis comparing current disease state as well as prospectively can be performed to determine if the Time Stamps, or subsets within, correlate with and/or are predictive of clinical course. Data collection would be completed over a 12-month period at a