The central circadian regulator of the brain, the suprachiasmatic nucleus (SCN), has been implicated in the pathology of sleep disorders. Deterioration of sleep consolidation, such as inappropriate or fragmented sleep, increases with age or dementia and is correlated with diminished amplitude of circadian signaling. A major cause is presumed to be loss of synchrony among individual SCN nuclei. A pharmacological treatment that shifts the phase of individual oscillators to better synchronize the SCN is predicted to increase the amplitude of circadian signaling and to have a powerful benefit in sleep therapy and mental health. BMAL1 is a central transcription factor within the circadian clock and is expressed in virtually all cells of the body. Certain orphan receptors, potential drug targets that have not been characterized at a pharmacological level, interact with the BMAL1 promoter. 1 of these receptors, localized predominantly in the brain and highly expressed in the SCN and pineal gland, is predicted to respond to lipophilic small molecules capable of crossing the blood-brain barrier. Ligands to this receptor would therefore be candidates to shift the phase of SCN output and to synchronize signaling of individual SCN nuclei by induction or suppression of BMAL1. To characterize the pharmacological potential of this target and initiate a long-term program of drug discovery, we plan to identify and characterize small molecule ligands.
The specific aims for this Phase I proposal are: (1) to identify and confirm hits that are active in both cell-based and cell-free assays by screening a small molecule library of 20,000+ compounds; (2) identify relatively selective ligands, including both agonists and antagonists, by additional cycles of compound acquisition and screening; and (3) characterize ligand activity in cell culture where circadian cycle or other circadiandependent changes in gene expression can be monitored. Successful completion of these aims will set the stage for focused development of lead compounds for testing in animal models of disease in Phase II. Relevance to Public Health. Insomnia and sleep disturbance contribute to occupational injuries, heart disease, and mental illness. Loss of synchrony between the body's internal clock and the environment, or a reduction in the amplitude of the body's normal circadian rhythm, is a major cause of sleep disorders. Current therapeutic approaches to better synchronize or enhance the function of the body's internal clock have limited effectiveness. A novel class of drug that effectively regulates circadian rhythm will have major value in treatment of jet lag, sleep disorders of shift work, and forms of insomnia due to depression, Alzheimer's disease, and aging that affect more than 10 million Americans each year.
