Humans and most other organisms manifest circadian (daily) rhythms which are controlled by an endogenous biochemical oscillator. Many cellular processes, including cell division, enzyme activity, and gene expression are timed by this oscillator. These """"""""biological clocks"""""""" are important to human physiology. For example, psychiatric and medical studies have shown that circadian rhythmicity is involved in some forms of depressive illness, """"""""jet lag,"""""""" drug tolerance/efficacy, memory, and insomnia. Therefore, understanding the biochemical mechanism of circadian clocks may lead to procedures which will be useful in the diagnosis and treatment of disorders which are relevant to sleep, mental health, and pharmacology. Despite the importance of clocked phenomena, however, the nature of the underlying biochemical mechanism remains elusive. Does it use or depend upon a known metabolic pathway, perhaps in a heretofore unsuspected way? Or is the circadian pacemaker driven by a totally unknown system? The biochemical mechanism of circadian oscillators is the most fundamental unanswered question in this field. This project will elucidate the molecular mechanism of this fascinating behavior by identifying molecular components of the circadian biological clock in a simple unicellular organism which can be manipulated genetically. The control pathway by which the circadian clock regulates the """"""""cab"""""""" gene will be analyzed. A reporter gene will be attached to the promoter of the cab gene so as to create an easily-manipulatable assay of this gene's expression. Other genes which are involved in the clock's central mechanism will be identified and cloned. The input photoreceptor pathway will be characterized by investigating the light-induced phase resetting of mutants of the phototransduction pathway. Simple unicellular organisms offer technical advantages which should accelerate the identification of cellular processes involved in the circadian oscillators of an organisms.
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