MYCENAE project team
INRIA Paris-Rocquencourt Centre
BP 105 - 78153 Le Chesnay Cedex - FRANCE
e-mail : Frederique.Clement@inria.fr
phone : +33 1 39 63 53 83 - fax : +33 1 39 63 57 86
REGATE Large Scale Project
Puisqu'on ne peut être universel en sachant pour la gloire tout ce qui se peut savoir sur tout, il faut savoir peu de tout, car il est bien plus beau de savoir quelque chose de tout que de savoir tout d'une chose. Cette universalité est la plus belle.
Blaise Pascal, Pensées
Main Research Topic
Mutiscale dynamics in the hypothalamo-hypophyso-gonadal axis
Brief physiological background
In vertebrates, the neuroendocrine axes play a major part in controlling the main physiological functions (metabolism, growth, development and reproduction) and integrating internal or external environmental factors. The gonadotrope axis is made up of the hypothalamus, belonging to the central nervous system, the pituitary gland and the gonads (ovaries in females, testes in males). The reproductive function is a complex, tightly controlled physiological function, subject to many environmental cues such as the daylength, food availability and social interactions, as well as to internal signals such as stress or metabolic status. Specific hypothalamic neurons secrete, in a pulsatile manner, the GnRH (gonadotrophin releasing hormone), the "conductor" of the gonadotrope axis. The pulsatile GnRH secretion pattern ensues from the synchronisation of the secretory activity of individual GnRH neurons. The release of GnRH into the pituitarian portal blood induces the secretion of the luteinising hormone (LH) and follicle-stimulating hormone (FSH) by the gonadotroph cells within the pituitary gland. The gonadotrophins LH and FSH control the development of germinal cells within the gonads and their secretory activity. In turn, hormones secreted by the gonads (steroid hormones such as androgens, progestagens and oestrogens or peptidic hormones such as inhibin) modulate the secretion of GnRH, LH and FSH within entangled feedback loops. In females, the GnRH secretion pattern dramatically alters once per ovarian cycle, resulting in the GnRH surge characterised by massive continuous release of GnRH. The GnRH surge is responsible for the LH surge that triggers ovulation, leading to the release of fertilisable oocytes from ovarian follicles selected for ovulation.
I am responsible for the coordination of the large scale project REGATE. REGATE lies at the border between Applied Mathematics, Control Theory and Computer Science on one hand, Physiology, Endocrinology and Cellular Biology on the other hand. It aims at disposing of interconnected, multi-scale models of the different organs building-up the gonadotrope axis and to be able to use them to take up physiological and clinical challenging questions. Starting from strictly biological motivations, the modelling approach gives rise to research questions in the fields of Applied Mathematics and Computer Science, dealing with the simulation and analysis of newly developed models or the solving of associated control problems. The project articulates on the coupling between different mathematical (mainly: conservation laws and dynamical systems) and computing (mainly: temporal logic and model checking) formalisms with biological knowledge and data.
Main publications in the field
- B. Aymard, F. Clément, M. Postel. Adaptive mesh refinement strategy for a non conservative transport problem. To appear in ESAIM: Mathematical Modelling and Numerical Analysis
- P.A. Fletcher, F. Clément, A. Vidal, J. Tabak, R. Bertram. Interpreting frequency responses to dose-conserved pulsatile input signals in simple cell signaling motifs. PloS One, 2014, 9(4): e95613.
- D. Monniaux, F. Clément, R. Dalbiès-Tran, A. Estienne, S. Fabre, C. Mansanet, P. Monget. The ovarian reserve of primordial follicles and the dynamic reserve of antral growing follicles: what is the link? Biology of Reproduction, ehead of pub.
- B. Aymard, F. Clément, F. Coquel, M. Postel. A Numerical Method for Transport Equations with Discontinuous Flux Functions: Application to Mathematical Modeling of Cell Dynamics. SIAM Journal on Scientific Computing, 2013, 35(6): A2442-A2468.
- F. Clément, D. Monniaux, P. Michel, T. Stiehl. Coupled somatic cell kinetics and germ cell growth: multiscale model-based insight on ovarian follicular development. Multiscale Modeling & Simulation, 2013, 11(3): 719-746.
- M. Krupa, A. Vidal, F. Clément. A network model of the periodic synchronization process in the dynamics of calcium concentration in GnRH neurons. The Journal of Mathematical Neuroscience, 2013, 3: 4.
- F. Clément, D. Monniaux. Multiscale modelling of ovarian follicle selection. Progress in Biophysics and Molecular Biology, 2013, 113(3): 398-408.
- F. Clément, J.-M. Coron, P. Shang. Optimal control of cell mass and maturity in a model of follicular ovulation. SIAM Journal on Control and Optimization, 2013, 51(2): 824-847.
- M. Krupa, A. Vidal, M. Derosches, F. Clément. Mixed-mode oscillations in a multiple time scale phantom bursting system. SIAM Journal on Applied Dynamical Systems, 2012, 11(4): 1458-1498.
- B. Aymard, F. Clément, F. Coquel, M. Postel. Numerical simulation of the selection process of the ovarian follicles. ESAIM Proceedings, 2012, 38: 99-117.
- A. Vidal, Q. Zhang, C. Médigue, S. Fabre, F. Clément. DynPeak : An algorithm for pulse detection and frequency analysis in hormonal time series. PloS One, 2012, 7: e39001.
- C. Rico, C. Médigue, S. Fabre, P. Jarrier, M. Bontoux, F. Clément, D. Monniaux. Regulation of Anti-Müllerian Hormone production in the cow: a multi-scale study at endocrine, ovarian, follicular and granulosa cell levels. Biology of Reproduction, 2011, 84(3): 560-571
- A. Vidal, F. Clément. A dynamical model for the control of the GnRH neurosecretory system. Journal of Neuroendocrinology, 2010, 22(12): 1251-1266.
- F. Clément, A. Vidal. Foliation-based parameter tuning in a model of the GnRH pulse and surge generator. SIAM Journal on Applied Dynamical Systems, 2009, 8(4): 1591-1631.
- A. Vidal, C. Médigue, B. Malpaux, F. Clément. Endogenous circannual rhythm in LH secretion: insight from signal analysis coupled with mathematical modeling. Philosophical Transactions of the Royal Society A , 2009, 367, 4759-4777.
- F. Clément. Multiscale modelling of endocrine systems: new insight on the gonadotrope axis. ESAIM Proceedings, 2009, 27: 209-226.
- X. Druart, J Cognié, G. Baril, F. Clément, J.-L. Dacheux, J.-L. Gatti. In vivo imaging of in situ motility of fresh and liquid stored ram spermatozoa in the ewe genital tract. Reproduction, 2009, 138(7): 45-53.
- C. Rico, S. Fabre, C. Médigue, N. di Clemente, F. Clément, M. Bontoux, J.-L. Touzé, M. Dupont, E. Briant, B. Rémy, J.-F. Beckers, D. Monniaux Anti-Mullerian hormone is an endocrine marker of ovarian gonadotropin responsive follicles and can help to predict superovulatory responses in the cow. Biology of Reproduction, 2009, 80(1): 50-59.
- N. Echenim, F. Clément, M. Sorine. Multiscale modeling of follicular ovulation as a reachability problem. Multiscale Modeling & Simulation, 2007, 6(3): 895-912.
- F. Clément, J.-P. Françoise. Mathematical modeling of the GnRH-pulse and surge generator. SIAM Journal on Applied Dynamical Systems, 2007, 6(2): 441-456.
- N. Echenim, D. Monniaux, M. Sorine, F. Clément. Multi-scale modeling of the follicle selection process in the ovary. Mathematical Biosciences , 2005, 198: 57-79.
- F. Clément, D. Monniaux, J.C. Thalabard, D. Claude. Contribution of a mathematical modelling approach to the understanding of ovarian function. Comptes Rendus Biologies, 2002, 325: 473-485.
- F. Clément, D. Monniaux, J. Stark, K. Hardy, J.C. Thalabard,
S. Franks, D.Claude. A mathematical model of FSH-induced cAMP production in ovarian follicles. American Journal of Physiology (Endocrinology & Metabolism), 281: E35-E53, 2001.
- C. Pisselet, F. Clément, D. Monniaux. Fraction of proliferating
cells in granulosa during terminal follicular development in high and low
prolific sheep breeds. Reproduction, Nutrition, Development, 40(3): 295-304, 2000.
- F. Clément. Optimal control of the cell dynamics in the granulosa of ovulatory follicles. Mathematical Biosciences, 152: 123-142, 1998.
- F. Clément, M.A. Gruet, P. Monget, M. Terqui, E. Jolivet,
D. Monniaux. Growth kinetics of the granulosa cell population in ovarian
follicles : an approach by mathematical modelling. Cell Proliferation,
30: 255-270, 1997.
- D. Monniaux, C. Huet, N. Besnard, F. Clément, M. Bosc, C. Pisselet,
P. Monget, J.C. Mariana. Follicular growth and ovarian dynamics in
mammals. Journal of Reproduction and Fertility, Suppl. 51: 3-23, 1997.
Former research topics
- Mathematical modelling and control of the cardiac electro-mechanical activity
I was responsible for the coordination of the cooperative research initiative ICEMA-2 and
ICEMA : Images of the Cardiac Electro-Mechanical Activity.
- Modelling and control of regulatory networks
I was involved in this field as a participant of the GDyn cooperative research action : Dynamical Analysis of genetic regulatory networks.
last update 03/25/2014