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SLEEP AND TEMPERATURE REGULATION

Diurnal protein expression in blood revealed by high throughput mass spectrometry proteomics and implications for translational medicine and body time of day

¹University Health Network, Toronto, Ontario, and Departments of Medicine, Physiology, and Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, and ²Toronto Sunnybrook Regional Cancer Centre, Division of Medical Oncology, and Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and ³Customized Online Biomathematical Research Applications, Charlottesville, Virginia

Submitted 13 March 2007 ; accepted in final form 28 May 2007

Molecular gene cycling is useful for determining body time of day (BTOD) with important applications in personalized medicine, including cardiovascular disease and cancer, our leading causes of death. However, it impractically requires repetitive invasive tissue sampling that is obviously not applicable for humans. Here we characterize diurnal protein cycling in blood using high-throughput proteomics; blood proteins are easily accessible, minimally invasive, and can importantly serve as surrogates for what is happening elsewhere in the body in health and disease. As proof of the concept, we used normal C57BL/6 mice maintained under regular 24-h light and dark cycles. First, we demonstrated fingerprint patterns in 24-h plasma, revealed using surface-enhanced laser desorption and ionization (SELDI). Second, we characterized diurnal cycling proteins in blood using chromatography and tandem electrospray ionization mass spectrometry. Importantly, we noted little association between the cycling blood proteome and tissue transcriptome, delineating the necessity to identify de novo cycling proteins in blood for measuring BTOD. Furthermore, we explored known interaction networks to identify putative functional pathways regulating protein expression patterns in blood, thus shedding new light on our understanding of integrative physiology. These studies have profound clinical significance in translating the concept of BTOD to the practical realm for molecular diagnostics and open new opportunities for clinically relevant discoveries when applied to ELISA-based molecular testing and/or point-of-care devices.

chronotherapy; biomarkers

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