Project Summary/Abstract All life on earth is governed by biological rhythms that are defined as self-sustained oscillations cycling with a fixed period. Biological clocks enable organisms to keep track of time and to adjust their physiology to recurring daily changes in the external environment, including nutrient and microenvironment status. Not surprisingly, lifestyle behaviors (e.g. shift work) that chronically de-regulate biological clocks are strongly associated with increased risk for a plethora of morbidities and diseases. Unbeknownst to many, in addition to the most well- characterized circadian rhythms (~24h oscillation), genes cycling with a 12h period were also prevalently found and evolutionarily conserved in multiple species ranging from circatidal marine animals, who adapt their rhythmic behavior to ~12h flow and ebb of the tides, to nematode C. elegans and mammals. Our group recently discovered that in mammals, the 12h rhythms are established by a dedicated 12h-clock that is evolutionarily conserved, cell- autonomous and independent from the circadian clock, but dependent on the unfolded protein response (UPR) transcription factor spliced form of XBP1 (XBP1s). However, the detailed regulation and functions of mammalian 12h-clock remains largely elusive. The overall aim of this proposal, thus, is to decode the regulation and functions of mammalian 12h-clock using a variety of innovative approaches. In addition to the application of field of chronobiology, the identification of novel regulators of the mammalian 12h-clock will most likely uncover new players implicated in stress responses and stress-associated pathologies. Likewise, new tools/approaches developed for the study of mammalian 12h-clock can also be broadly applied to these research areas.