Circadian rhythms are fundamental to life. In humans, circadian rhythms govern the timing of our sleeping and eating habits. When these rhythms are disrupted, either by disease or environmental conditions, human health is compromised. Chronic conditions such as depression, cancer, and obesity have been linked to disruptions in the core molecular clock that drives rhythms. By studying circadian rhythms in a simple model system, such as the fruit Drosophila melanogaster, we will improve both our understanding of the genes that control circadian rhythms as well as our ability to treat and prevent chronic and lifethreatening illnesses that are caused by abnormal function of circadian genes. Protein kinase CK2 plays an important role in regulating the period length of circadian rhythms in Drosophila melanogaster. The goal of the proposed study is to identify the molecular mechanisms by which CK2 regulates TIMELESS (TIM), a core clock protein. TIM determines period length of the molecular clock, in part, by regulating stability of its heterodimeric partner, PERIOD. We hypothesize that CK2 normally destabilizes TIM by directly interacting with and phosphorylating TIM, thus promoting its degradation. We will use well-established circadian behavioral assays and molecular biological techniques in our studies. By making site-directed tim mutants and analyzing the effects of these mutations on behavioral and molecular rhythms, we will be able to determine the identity and function of CK2 phosphorylation sites in TIM. These studies are very feasible, as our laboratory has used all of these techniques previously to identify PERIOD as a substrate of CK2. An enhanced understanding of the role of CK2 in circadian rhythms may be of particular importance for understanding and treating Seasonal Affective Disorder, a recurring type of "winter depression" that shows similarities to phenotypes exhibited by flies in which CK2 function is decreased by genetic mutation. [unreadable] [unreadable]