Analysis of Mammalian Circadian Mechanism with Cell-permeant Clock Proteins

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DESCRIPTION (provided by applicant): Humans and most other organisms manifest circadian (daily) rhythms that are controlled by an endogenous biochemical oscillator that regulates the timing of sleep, cardiovascular functions, and metabolism. 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, insomnia, and other sleep disorders. Therefore, understanding the biochemical mechanism of circadian clocks may lead to procedures which will be useful in the diagnosis and treatment of disorders that are relevant to sleep, mental health, and pharmacology. The salient properties of circadian clocks-24 hour time constant, high precision, temperature compensation-are presently impossible to explain biochemically. The current Transcription and Translation Feedback Model for circadian rhythms posits that rhythmic clock protein abundance is critical for clock function. In model systems, it has been possible to reset the phase of circadian rhythms by induction of clock protein synthesis at specific phases. This approach has been difficult to accomplish in mammalian systems. The current project will test hypotheses concerning the significance of rhythmic clock protein abundance in mammals by using new methods to introduce proteins directly into cells by peptide-mediated transduction across cell membranes. This technology will allow us to modulate the intracellular concentration of clock proteins in cells, tissue slices, and intact animals. This project is appropriate for the NIH Exploratory/Developmental Grant (R21) Program because it fulfills all of the following primary criteria: (1) innovative research directions, (2) exploration of approaches that are new to a substantive area, and (3) development of new technologies and methods. PUBLIC HEALTH RELEVANCE: Rigorous testing of the current model for circadian oscillators is crucial for our understanding of these biological clocks that control so much of human physiology. These studies will yield results of theoretical importance, but recent evidence also implicates sleep disorders, obesity, cardiovascular disease, and cancer when normal circadian clock function is disrupted. Therefore, these studies also have the potential for designing treatments for sleep disorders, jet lag, insomnia, cardiovascular disease, and other clock-related disorders.