Current research in my lab focuses on the integrative analysis of circadian systems in mammals using rodent models. Using reporter gene tools and a variety of methods for measuring organ function and behavior, our goal is to develop an understanding of whole-organism rhythmicity and how it relates to both healthy and abnormal function.
Circadian rhythmicity (the ability of living systems to undertake periodic functions in cycles of 24 hours) is a fundamental property of life. Circadian rhythms are present in all organisms from bacteria to mammals and they are all based upon auto regulatory feedback loops of “clock” gene expression.
There are currently three specific projects in the lab:The first aims to study how the circadian system to copes with manipulations of the environmental signals. We, together with Gene Block, Mike Menaker and colleagues at the University of Virginia, have discovered that aged mice submitted to repeat shifts of the light schedule (similar to a weekly transmeridian travel or rotating shiftwork) die sooner than mice kept under normal light-dark cycles. We are investigating the mechanisms that accelerate death, and have recently become focused on the innate immune system as a target for jet lag, even in young mice. This may serve as a model which we can use to understand the serious negative health consequences of shift work.
Manipulations of the circadian system can either enhance or inhibit cancer initiation and progression. The second main project in my lab addresses how manipulation of circadian rhythms impact the development and progression of malignancies. Our early studies indicate that rat hepatocellular carcinoma, or liver cancer, expresses an endogenous circadian rhythm, and this rhythm is different from the rhythms measured from adjacent healthy host tissue. Our current studies in mice are focused on colorectal cancer. We are integrating luciferase reporters for circadian clock genes into tumors in order to monitor in real time the circadian ‘behavior’ of the tumors during manipulations of the host circadian rhythms. We trying to determine how manipulations such as chronic jet lag, constant light, and restricted feeding alter tumor growth, in the hopes that this information can be used to prevent, or better treat cancers in humans.
The suprachiasmatic nucleus (SCN) in the hypothalamus serves as a master circadian clock for mammals. It receives direct retinal input and communicates this information to other clocks located throughout the organism, thereby influencing every circadian rhythm in the body. The third project in the lab uses multiposition automated bioluminescence imaging (MABI) to dynamically record gene expression in multiple brain slices, each containing a portion of the SCN. Using this new approach we are developing a three-dimensional view of how rhythms in the SCN are organized. The SCN, as it turns out, exhibits a high degree of spatial complexity, much like other brain regions which contain maps of the body or external space.
Research Key Words: Circadian rhythms, jet lag, cancer, immune system