Virtually all eukaryotic organisms appropriately examined have been shown to possess the capacity for endogenous temporal control and organization known as a circadian rhythm. The cellular machinery responsible for generating this ability is collectively known as the biological clock. The importance of a detailed understanding of the circadian clock to our understanding of physical and mental health and the treatment of mental illness rests on the ubiquity of its influence on human mental and physiological processes. These range from circadian changes in basic physiological functions to the clear involvement of rhythms in human work rest cycles and sleep. Human psychiatric illnesses known to be a direct result of clock malfunction include common forms of manic-depressive illness and insomnia. Extensive research has demonstrated the significance of clock control of gene expression, but little is known regarding how clocks control the behavior of the cells in which they operate. One salient aspect of this regulation is clock control of mRNA abundance. We have identified """"""""ccg"""""""" genes that are unequivocally under circadian clock control, and we are now using genetic and biochemical approaches to identify the cis- and trans-acting factors conferring clock regulation.
In Specific Aim 1 we will complete the identification of the trans-acting factors that mediate clock-controlled activation and repression of downstream genes. We have identified several novel ccgs including a gene, ccg-9, required to mediate clock regulation of downstream genes.
In Specific Aim 2 we will determine the identity of novel ccgs and will study the mode of action of CCG-9, in particular, to understand how it mediates clock regulation and how it is regulated by factors in or next to the oscillator. We have developed a strong conceptual base in genomics and have begun the elucidation, via high through-put sequencing, of the global morning versus evening gene expression pattern in a simple cellular oscillator. Further, we now understand in broad outline how the clock works, what some clock genes look like, and enough about what characterizes their behavior that we can evaluate novel genes in a new system.
In Specific Aim 3 we will (1) clone and characterize additional clock genes, (2) complete the identification of morning versus evening genes in Neurospora, and (3) extend this technology to a more complex cellular oscillator in a mammalian system by examining morning versus evening gene expression in the mouse SCN.
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