11-13 May 2012 Helsingør - Denmark www.networkbio.org

KRzYSzTOf fUJAREWICz
SILESIAN UNIVERSITY Of TEChNOLOGY, POLAND
Optimal sampling for parameter estimation of cell signaling pathway models based on multivariate measurements
Mathematical modeling of cell signaling pathways became a very important and challenging problem
in recent years. The importance comes from possible application of obtained models. It may help us to
understand phenomena appearing in single cells and in cell populations. Furthermore, it may help us with
discovering new drug therapies.
Mathematical models of cell signaling pathways take different forms. The most popular way of mathematical
modeling is to use a set of nonlinear ordinary differential equations (ODEs).
Usually there are many hypotheses about the structure of the model (set of variables and set of phenomena).
It leads to several rival models and one of them should be chosen among others. This choice may be
supported by so called T-optimal experiment design.
The next step, estimation of the model’s parameters, is also very complicated because of the nature of
measurements. The blotting technique usually gives only semi-quantitative observations which are very
noisy and they are collected only at limited number of time moments. Once more, the accuracy of parameter
estimation may be significantly improved by proper experiment planning.
We present two-stage experiment plan optimization algorithm. The first step is gradient-based D-optimization
procedure to find all stationary points. The second step is pair-wise replacement for finding optimal
numbers of replicates of measurements. The algorithm is applied to one of cell signaling pathway model,
known from the literature.
For multivariate measurements the presented approach gives, in general, different optimal time points for
different variables. In practice it is better to take measurements at the same time points. We show how this
constraint influences the final result of optimization.
This work has been supported by Polish Ministry of Education and Science under grant N N514 411936.
abStractS For PoSterS abStractS For PoSterS
IA VAN DIJK, MJ OUDhOff, J VAN DE AMEIDE, JGM BOLSChER, ECI VEERMAN.
DEPARTMENT Of ORAL BIOChEMISTRY, ACADEMIC CENTRE fOR DENTISTRY AMSTERDAM (ACTA), UNI-
VERSITY Of AMSTERDAM AND VU UNIVERSITY AMSTERDAM, ThE NEThERLANDS.
Histatin from saliva promotes wound healing: Salivary peptide histatin induces GPCR- and ERK-dependent
cell migration
Wounds in the oral cavity heal faster than at other sites in the human body, e.g. the skin. Several factors
have been implicated in this phenomenon, including the presence of saliva, which in rodents is a reservoir of
many growth factors, such as epidermal growth factor (EGF) and nerve growth factor (NGF). In humans the
identity of the involved compounds has remained elusive, since the saliva concentration of growth factors is
1,000 to 100,000 times lower than in rodent saliva. The present study was aimed at the identification of the
factor(s) responsible for the alleged wound healing power of saliva, and a first characterization of the cellular
processes.
Using an in vitro scratch assay we found that human saliva is able to induce epithelial cell migration, without
involvement of EGF. By testing protein fractions of human saliva obtained by HPLC, we identified salivary
histatins as the main migration-inducing factors in saliva. The ᴅ-enantiomer of histatin is not active, pointing
towards the involvement of a stereospecific receptor. N-to-C terminal cyclization of histatin potentiates the
molar activity approximately 1,000-fold, suggesting that the activation of the putative receptor requires a
specific spatial conformation of the peptide. Histatin activity was abolished both by inhibition of mitogen activated
protein kinases ERK1/2 and MEK, and by pertussis toxin, an inhibitor of G protein coupled receptors,
suggesting the involvement of a GPCR-dependent ERK1/2 signaling pathway. Using a functional phosphokinase
assay, we found, in addition, activation as well as inhibition of a large number of other phosphokinases
upon treating epithelial cells with histatin.
Conclusion: Our results emphasize the importance of histatin in human saliva for tissue protection and recovery,
and establish the experimental basis for the development of synthetic histatins as novel wound-healing
agents.
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