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. Circadian rhythm generation consists of an approximate 24 h rhythmic pattern of physiologic regulation whereby proper regulation of the expression is critical to maintaining good health. Disturbances in circadian rhythm generation appear to be associated with many diseases such as seasonal affective disorders, a variety of other mental illnesses, sleep problems, cancer, and a number of metabolic syndromes. It is possible that circadian disruptions have some causative role in the pathogenesis of several of these diseases, as there is evidence suggesting links between genetic factors related to abnormal circadian rhythm generation and illnesses like bipolar affective disorder, familial advanced sleep phase syndrome, and delayed sleep phase syndrome. Even though associations between circadian rhythm disturbances and several diseases have been reported in humans, the precise mechanisms by which circadian rhythm generation impacts the manifestation of disease remains unknown for many illnesses and disorders. Among the limiting factors are technical difficulties related to the physiological measurement of human circadian rhythm expression. To better understand human circadian rhythm generation in patients, the implications of circadian rhythm disturbances in pathogenesis, as well as to evaluate potential pharmaceutical treatments, it is important to develop a non-invasive, simple, rapid and reliable in vitro assay to determine circadian rhythm in humans. Recent findings have enabled investigators to demonstrate the feasibility of using peripheral cells to analyze human circadian rhythm. So far, the dermal fibroblast is the only peripheral cell in which stable circadian rhythm can be recorded in humans. However, skin biopsy is not a routine procedure in most clinical departments;they also are painful for patients and often leave scars. Therefore, it would be beneficial to develop an assay system using some other cell type (i.e., a blood cell). In the present proposal, we aim to develop a non-invasive, in vitro assay system to measure human circadian rhythm in macrophages derived from human blood samples, using real-time monitoring of circadian parameters with a clock gene reporter (a total of 31 healthy subjects will be recuited). Once the assay system is established, this technique will be applied to evaluate the effects of chemicals, thereby testing the feasibility of this assay as a future diagnostic tool (a total of 30 paritipants will be recuited). The CRC will be utilized to recruit healthy volunteers and collect blood samples for the above purpose. Each participant will be asked to donate 5 mL blood twice, at least one month apart.
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