Circadian rhythms are mechanisms that measure time on a scale of about 24 hours and then adjust the body to environmental signals. Circadian clock genes produce proteins that are necessary for the generation and regulation of circadian rhythms. These proteins also regulate genes involved in either cell division or cell death. Agitation in the balance between cell division and cell death will lead to cellular dysfunction. In this project, the investigator will use an interdisciplinary approach that combines biological, mathematical, and bioengineering tools, to examine the circadian factors that act as mediators in the interconnected network that controls the circadian clock. This project includes an educational component that will recruit, retain, train, and graduate a more academically prepared student body with a global vision of interdisciplinary research and world opportunities, creating a new sense of leadership.
This project uses multidisciplinary and complementary methods to establish signature events that modulate the effect of genotoxic stress in both cell division and circadian phase resetting across length scales from molecular to cellular systems. Initially, the study will focus on intracellular events that dynamically adapt themselves to genotoxic or physiological challenges to what cells are exposed to. Then, the study will shift toward understanding how redistribution of clock and checkpoint players influence the clock itself and promotes resetting. To accomplish this goal, the investigator will integrate diverse experimental observations and measurements into mathematical models that simulate concrete and realistic experiments, reconcile measurements and current data, and illuminate how different components cooperate to produce a particular behavior. Lastly, additional experiments will be designed to explore the influence of the microenvironment and systemic factors in the clock response to genotoxic stress and to the circadian behavior of multi-cell arrangements in three-dimensional substrates. As a result, the investigator proposes to: (1) determine how spatial/temporal organization of circadian components modulates the cellular response to genotoxic stress and provokes clock resetting; and (2) study the behavior of circadian oscillatory systems challenged by genotoxic stress in 3D biomimetic environments. The transition to a system that more closely resembles physiological conditions will expose additional critical parameters and provide a more comprehensive map of crosstalk mechanisms, help predict network connections, and generate new testable hypotheses.
