GENE SILENCING IN THE RHESUS MACAQUE USING LENTIVIRAL VECTORS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Major physiological functions, such as metabolism, thermoregulation, sleep, and response to stress, all have a circadian rhythm. Moreover, disruption of these rhythms is thought to contribute to the etiology of perturbed sleep-wake cycles in the elderly and to Seasonal Affective Disorder (SAD). However, the underlying neuroendocrine mechanisms responsible for coordinating rhythmic functions in humans are poorly understood. Recently, my laboratory discovered that circadian rhythms in the rhesus monkey are controlled not only by a central pacemaker, located in the suprachiasmatic nucleus (SCN) of the brain, but also by peripheral oscillators in the adrenal gland, liver and kidneys. Taken together, these novel findings imply that normal physiological functions are regulated by coordinated actions of several distinct biological clocks, and that various disease states may stem from abnormal phase relationships between them. To develop effective therapies for circadian-related disorders in humans, we need to have a deeper understanding of the molecular mechanisms responsible for circadian rhythm generation in primates, and a deeper understanding of how peripheral oscillators synchronize their rhythmic activity. The goal of this pilot study is to develop an effective way of selectively silencing specific body clocks. This powerful tool would enable us to systematically examine the contribution of the various peripheral oscillators to normal physiology and to lay the groundwork for future development of therapies for circadian-related disorders.