AN INTERDISCIPLINARY STUDY OF DELAYED SLEEP PHASE DISORDER

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DESCRIPTION (provided by applicant): Circadian rhythm sleep disorders constitute up to 15% of diagnosed cases of insomnia, with Delayed Sleep Phase Disorder (DSPD) representing a large majority of such cases. Diagnosis and treatment of these sleep phase disturbances are hampered by a remarkable paucity of data addressing key aspects of the disorders, including a virtual absence of studies that adequately characterize the sleep disturbance, itself. The pathophysiology underlying DSPD remains largely theoretical in scope, due also to a lack of data shedding light on this issue. Advances in the identification of genetic markers for circadian rhythm sleep disorders, combined with established methods for studying human sleep and biological rhythms, offer exciting avenues in the study of circadian rhythm sleep disorders. The aim of this study is to use an interdisciplinary approach to enhance our understanding of such disorders, and that of normal sleep regulation. We will test the hypotheses that individuals diagnosed with DSPD will exhibit 1) spontaneous period lengths (tau) that are significantly longer than normal controls; 2) altered phase relationships between sleep and body temperature that contribute to reduced sleep quality; 3) variations in one or more of the canonical clock genes as well as aberrant molecular tau. Finally, we hypothesize that across both groups (DSPD and normal controls), behavioral (sleep/wake, actigraphy) and physiological (body temperature, melatonin) measurements of tau will be positively correlated with molecular measurements of tau. Forty subjects (20 diagnosed with DSPD, 20 normal controls) will undergo a laboratory protocol consisting of entrained and "free-run" components, during which sleep and circadian variables are continuously recorded. 'Molecular' tau will be measured in cell cultures derived from fibroblasts, by tracking rhythmic expression of clock loci using RT-PCR techniques, and by analyzing the expression of a circadian clock-driven luciferase reporter. Analyses will focus on hypothesized differences in tau between DSPD, and normal controls, on the characterization of sleep in DSPD, on examination of the relationships between sleep quality and circadian phase-angle, and on the examination of hypothesized relationships among circadian measures assessed at the behavioral, physiologic and molecular levels. This work will be the first to use such an interdisciplinary approach to better characterize and understand normal and pathological circadian sleep regulation at the behavioral and physiological levels, while gaining important insights into the genetics that underlie circadian timing of the human sleep/wake system.