1. boolean Here, we are focusing on the early steps of FSH-induced signalling: the FSH receptor transduction mechanisms. We have translated the model previously described by Clément et al. (1) in the BIOCHAM environment. BIOCHAM is a formal language for modeling bio-molecular systems at 3 abstraction levels: - boolean (presence/absence of molecules), pathways, temporal properties - concentration (molecule concentration/activity), ODEs - stochastic (number of molecules), continuous time Markov Chains Free software available at http://contraintes.inria.fr/BIOCHAM/http://contraintes.inria.fr/BIOCHAM/ MODEL cell signaling network induced by Follicle Stimulating Hormone (FSH) receptors binding, receptor configuration changing and synthesis of cAMP. Rules of the model: kinetic expressionforbiochemical reactionbiological phenomenon (MA(k1*FSH),MA(k2))forR R-FSH.Ligand binding to the receptor MA(beta*sigma)forEFSH =[R-FSH]=>2*EFSH.Adenylyl cyclase activation MA(beta)forEFSH => _.Adenylyl cyclase desactivation MA(k4)for _ =[EFSH]=> cAMP.cAMP generation MA(k5)for cAMP => AMP.cAMP degradation MA(rho)for R-FSH => R~{P}-FSH.Receptor phosphorylation (desensitization) MA(k7) for R~{P}-FSH => R~{P}.Receptor internalization MA(k8) for R~{P} => R.Receptor recycling Parameters & Initial Conditions : parameter(beta,0.1). present(R,1.536). … Specification: conservation({R, R~{P}, R-FSH, R~{P}-FSH}). DIAGRAM OF BIFURCATION with XPPAUT - export_ode from BIOCHAM. - put the initial condition to the equilibrium point - trace the bifurcation diagram with AUTO ESTIMATION OF HOPF BIFURCATION PARAMETER with MAPLE 0.0529254 < beta_HP < 0.0529255 CONSTRAINT-BASED SEARCH for rules and parameters - boolean semantics: Ai(EF(FSH-R~{P})) is true Ai(AG(!(FSH-R~{P})->checkpoint(FSH-R,FSH-R~{P}))) is true - numerical semantics:get_period_from_trace(R-FSH). Period of R-FSH is 146.85984322 (10 2 s) learn_parameters([beta],[(0.0529254,0.1)],100,period(R-FSH,146.85984322),1000). parameter(beta, 0.059045098). POINCARE MAP, RETURN TIME and VELOCITY with XPPAUT R-FSH = 1 and dR-FSH/dt>0 T in {3.3, 165.4, 317.1, 465, 612.1, 759.1, 906.1} Phase plane with several values for beta Bifurcation Diagram Velocity BIOCHAM CTL BIOLOGICAL PROPERTIES MODEL MAPLE Rule search Parameter search concentration PCTL LTL F. Clément 1, F. Fages 2, D. Heitzler 3 and E. Reiter 3 1 SISYPHE; 2 CONTRAINTES, INRIA Rocquencourt, 78153 Le Chesnay Cedex; 3 UMR6175 PRC, 37380 Nouzilly. Simulation MODELING OF FSH SIGNALING NETWORK IN OVARIAN FOLLICLE CELLS WITH BIOCHAM Simulation Generated diagram stochastic XPPAUT INTRODUCTION Our project aims at applying a system biology approach to the modeling of the cell signaling network induced by Follicle Stimulating Hormone (FSH). More specifically, we use the biochemical modeling environment BIOCHAM to : - construct a model of signaling networks induced by FSH in its target cells under different physiological circumstances - specify in temporal logic the biological properties of the system - understand how FSH-induced signaling translate into the appropriate biological outcomes (namely: proliferation, differentiation or apoptosis of the target cells) - integrate the intracellular model into an already available multi-scale model of ovulation. FSH Somatic cells of the gonads Proliferation Apoptosis Differentiation Signaling network ? REFERENCES [1] F. Clément, D. Monniaux, J. Stark, K. Hardy, J. C. Thalabard, S. Franks and D. Claude Mathematical model of FSH- induced cAMP production in ovaian follicles. AJP – Endo 281:35-53 (2001). [2] Fages, F., Soliman, S. and Chabrier-Rivier, N. Modeling and Querying Interaction Networks in the Biochemical Abstract Machine BIOCHAM. Journal of Biological Physics and Chemistry 4 (2): 64-73 (2004). ACKNOWLEDGEMENTS This project is funded by INRA (ACI AgroBI 2006-2008). Domitille Heitzler is an ASC (Assistant Scientifique Contractuel) from INRA. Query evaluation