Physiologically based modelling of circadian control on cell proliferation

The molecular circadian clock which is present in almost all cells of animal organisms exerts a control on the cell division cycle in proliferating tissues by modulating the activity of cyclins and cyclin dependent kinases (CDKs), the proteins which determine transitions from one phase of the cell cycle to the following one, until effective division. Each peripheral cell circadian clock is under the synchronising control of a central hypothalamic pacemaker which itself receives inputs, synchronising or disruptive, from external light and from circulating molecules such as cytokines. Principles for modelling these interacting systems are exposed. They rely on age-structured partial differential equations for cell proliferation in a population of cells and ordinary differential equations for the control of cell cycle phase transitions and for the circadian system presented as a network of oscillators with synchronisation and desynchronisation. These physiological cellular systems are coupled together and subject to pharmacological inputs, e.g. from anticancer therapies, which may be synchronised with cell cycle timing by the knowledge of the body circadian clock status, investigated by noninvasive measurements. The output of the controlled cell proliferation is a population growth exponent identifiable by in vivo tissue measurements; it allows to assess the proliferative status of the tissues under investigation, as a function of the circadian clock status, well fit or disrupted, and of pharmacological inputs such as used in anticancer treatments