A combination of computational and neurobiological methods will be used to explore the mechanisms which generate endogenous daily (circadian) rhythms in a mammal. The master circadian pacemaker, which resides within the suprachiasmatic nucleus of the hypothalamus (SCN), is comprised of thousands of cell-autonomous oscillators. One objective of this work is to establish a brain slice preparation in which a luciferase reporter allows us to track oscillations in the expression of critical clock genes in real time. The researchers will focus on identified transcriptional-translational feedback loops of genes whose expression is critical to circadian rhythmicity. Molecular methods will be used to selectively neutralize the expression of specific genes, and to examine the effects of such manipulations on the pacemaker and subordinate oscillators. In particular, the relationship between the master oscillator and its damping slaves in the subparaventricular zone will be investigated; the later comprises the major output of the SCN through which the central clock regulates much of the physiology and behavior of the rest of the organism.
The intellectual merit of this work is centered upon coordination of the computational modeling with neurobiological and molecular approaches. It will extend to interactions among distributed oscillators. The broader impact of this work includes its application to understanding the health-related conditions arising from jet lag and shift work. Furthermore, this research will be carried out both at the University of Massachusetts at Amherst and at Smith College, the nation's largest liberal arts college for women. Undergraduate and graduate students will have opportunities to conduct hands-on experiments using state-of-the art equipment, working with mentors who are active researchers. This collaborative efforts will offer opportunities for women and under-represented minorities to gain training at the cutting edge of mathematics, science and engineering. The instructional efforts will be integrated with the newly formed Picker Engineering Program at Smith College. Regular meetings will be held, at which students and faculty review the current literature on biological clocks. The collaborative and interdisciplinary nature of this research draws together students and faculty from diverse backgrounds including Neuroscience, Biology, Computer Science, and Engineering.
