The circadian clock is running autonomously, i.e. without external stimuli. The regular daily rhythm is generated on a single cell level as a product of molecular machinery of periodically activated and inactivated clock genes. The central clock in the suprachiasmatic nucleus is a network of individual clock cells that receives information about external time, as in order to successfully predict regular daily changes in the environment, the clock must be entrainable (time-adjustable). We explore the entrainment of the clock and its disorders on various experimental models in vivo and in vitro.

The clock in the suprachiasmatic nuclei - our laboratory was among the first to demonstrate the molecular mechanism for encoding information about the photoperiod (i.e. the length of the light part of the day, which changes during the year in our climate) in both the central and peripheral clock.

The clock in the large intestine (colon) - our laboratory was the first to describe the circadian clock at the molecular level in the lining of the colon. These clocks are entrained by food intake and the passage of chyme and regulate a number of site-specific physiological processes.

Clock gene expression in the epithelium of the rat colon.

Entrainment of the circadian clock in vitro - as models, we use transgenic PERIOD2::Luciferase mice (see insert) or cell cultures with added reporter (clock regulated segment of DNA linked to luciferase gene), which allow us to directly monitor the clock at the molecular level. The clock can be entrained for example by using an external temperature cycle or various biologically active substances.

PERIOD2::Luciferase knockin mouse
A transgenic mouse, in which, through the means of a specific recombination (knockin), a gene for one of rhythmically regulated clock proteins (Period2) was replaced for the same gene fused together with the gene for the enzyme luciferase. Luciferase is responsible for the catalysis of reactions allowing luminescence of fireflies. Therefore, in the presence of a substrate (luciferin), the cells and tissues of the mice luminesce in a regular circadian rhythm. This allows us to accurately and non-invasively examine the clock mechanism and its responses to stimuli in real time at a molecular and cellular level.

Entrainment of the cellular clock by a temperature cycle.

The health importance of temporal regulation of bodily processes - metabolic disorders and cancer

The circadian system, metabolism and cell cycle are interrelated and changes in one system may affect the other; chronic disruption of the timing system may for example lead to development of serious metabolic disorders such as diabetes and metabolic syndrome and increased incidence of various cancers.

Our laboratory investigates the connection between these systems on various models.

The circadian system of hypertensive rats - our laboratory has shown that the circadian system of hypertensive inbred rat strain has different characteristics compared to healthy Wistar. We investigate whether these differences may be related to the development of metabolic disorders.

The role of the circadian system in the pathogenesis of colorectal cancer (in collaboration with the Department of the Epithelial Function). We use various models (cell and tissue cultures, induced or subcutaneously transplanted tumors in immunosuppressed transgenic mice) to determine, whether the disruption of the circadian system is associated with increased formation of tumors in the colon.