Michael A. Henson Group

Multiscale Modeling and Analysis of Circadian Rhythm Generation and Synchronization

The objective of this interdisciplinary project is to develop an integrated experimental, modeling, and computational program to decipher the molecular mechanisms responsible for mammalian circadian rhythm generation and synchronization. Our initial computational work involves the construction of a multicellular molecular model that employs the neurotransmitter vasoactive intestinal polypeptide (VIP) as the synchronizing biochemical species. The release of VIP from individual cells is hypothesized to be rhythmic and light dependent. A heterogeneous cell ensemble including both intrinsically rhythmic pacemakers and damped oscillators exhibits experimentally observed behavior such as self-synchronization, entrainment to ambient light-dark cycles, and desynchronization in constant bright light. These simulations suggest that intercellular coupling allows coherent timekeeping with large heterogeneous populations of relatively imprecise pacemaker cells. Our current work is focused on the development and analysis of small world intercellular networks for robust synchronization of heterogenenous cell populations.

Funding: NIGMS

Student: Tsz-Leung To (B.S.), Christina Vasalou (3rd year Ph.D.)

Collaborator: Profs. Frank Doyle, Linda Petzold and Guillaume Bonnet (UCSB), and Erik Herzog (Washington University)

Publications and Recent Presentations:

1. To, T., M. A. Henson and F. J. Doyle III, "Modeling the Synchronization of Biochemically Coupled Circadian Oscillators," Proceeding of Foundations of Systems Biology and Engineering, Santa Barbara (2005).
2. To, T., M. A. Henson, E. D. Herzog and F. J. Doyle III, "A Mathematical Model for SCN Synchronization in the Mammalian Circadian Clock," 10th Biennial Society for Research on Biological Rhythms Conference, Sandestin, FL, May 2006.
3. To, T.-L., M. A. Henson, E. D. Herzog and F. J. Doyle III, "A Molecular Model for Intercellular Synchronization in the Mammalian Circadian Clock," Biophysical Journal, 92, 3792-3803 (2007). [PDF]
4. Henson, M. A. "Molecular Level Modeling and Dynamic Systems Analysis of Coupled Multicellular Systems," Proc. Foundations of Systems Biology and Engineering, Stuttgart, Germany (2007).
5. Vasalou, C., G. M. Freeman, E. D. Herzog and M. A. Henson, "Small World Network Models of Intercellular Coupling in the Suprachiasmatic Nucleus," 11th Biennial Society for Research on Biological Rhythms Conference, Sandestin, FL, May 2008.