Post-Doctoral Research Visit F/M Post-doctoral position in mathematical and/or computational biology : Coupling structured population dynamics models with physiologically-based pharmacokinetic models to assess reproductive fitness

The Inria Saclay-Île-de-France Research Centre was established in 2008. It has developed as part of the Saclay site in partnership with Paris-Saclay University and with the Institut Polytechnique de Paris .

The centre has 39 project teams , 27 of which operate jointly with Paris-Saclay University and the Institut Polytechnique de Paris; Its activities occupy over 600 people, scientists and research and innovation support staff, including 44 different nationalities.

The impact of micropollutants on living organisms is a major concern, whether at the individual or population level. Due to their living environment and their physiology, fish are particularly exposed to these micro-pollutants and in particular to endocrine disruptors (ED). They therefore constitute sentinel species for detecting and understanding the multiscale reprotoxic effects of EDs and their adverse outcomes on the reproductive fitness from the individual up to the population levels.  

The field of toxicology, and more generally eco-toxicology, has recently acquired methodological tools, such as  qAOP (quantitative Adverse Outcome Pathways), based on dynamic models with quantitative outputs to rigorously assess the effects of EDs from available experimental data and knowledge (Conolly et al. 2017). qAOP models can predict ED effects  in silico and be used both for basic research and regulatory purposes, while limiting the use of laboratory animals.

The postdoc work will be dedicated to enriching a qAOP model developed by the hosting team and collaborators. The first task will consist in coupling a size-structured (PDE-based) mechanistic model of oogenesis (the developmental process leading to the release of a fertilizable femate gamete), considering all maturation stages and their control (Bonnet et al. 2020, Ballif et al. 2024), with a physiologically-based pharmacokinetic (compartmental ODE-based) model representing the hormonal dynamics within the reproductive (hypothalamo-pituitary-gonadal) axis (Pery et al. 2014, Ly et al. 2023). The coupling will be based on careful mapping of functions involved in the different models, addition of missing variables when needed, and timescale separation when possible to enforce model parcimony.  The second task will be to design appropriate numerical schemes to simulate the model in both physiological and toxicological  situations (exposure to EDs) and perform an extensive parameter estimation and sensitivity/identifiability analysis. The calibrated coupled models will enable a detailed assessment of reprotoxic effects, in particular long-term effects and rebound/compensation mechanisms affecting the oocyte population and hormonal feedback loops.

If time allows, and according to the interest of the post-doctoral candidate, we will tackle a qualitative analysis of the coupled model to shed light onto the structural influence of parameters on the model behavior and the related impact on the reproductive function.

References

G. Ballif, F. Clément and R. Yvinec, Nonlinear compartmental modeling to monitor ovarian follicle population dynamics on the whole lifespan, J. Math. Biol., 89:9, 2024.
C. Bonnet, K. Chahour, F. Clément, M. Postel, R. Yvinec. Multiscale population dynamics in reproductive biology: singular perturbation reduction in deterministic and stochastic models. ESAIM Proc. Surveys, 67: 72-99, 2020.
R.B. Conolly, G.T. Ankley, W.Y. Cheng, M.L. Mayo, D.H. Miller, E.J. Perkins, D.L. Villeneuve, K.H. Watanabe. Quantitative adverse outcome pathways and their application to predictive toxicology. Environ. Sci. Technol., 51(8):4661–4672, 2017.
T.-K. Ly, J. De Oliveira, E. Chadili, K. Le Menach, H. Budzinski, A. James, N. Hinfray, R. Beaudouin. Imazalil and prochloraz toxicokinetics in fish probed by a physiologically based kinetic (PBK) model, 04 December 2023 (preprint available at 10.21203/rs.3.rs-3580808)
A. Pery,  J. Devillers, C. Brochot, E. Mombelli, O. Palluel , B. Piccini , F. Brion, R. Beaudouin.  A  Physiologically - Based Toxicokinetic Model for the Zebrafish Danio rerio. Environ. Sci. Technol., 55848: 781-790, 2014.

Read and synthesize literature work
Complete and couple existing models.
Identify timescale differences in the dynamics to reduce the complete model
Develop and implement numerical schemes suited for the coupled model
Perform parameter estimation, sensibility/identifiability analysis
Write and disseminate the results to the scientific community

Ph.D in applied Mathematics or computational biology, with expert knowledge in numerical simulation of ODEs and PDEs in standard code language (e.g. such as R, Python, Julia, C).
Experience with either sensitivity/identifiability analysis or parameter estimation will be greatly appreciated.
Strong motivation for biological applications and work in an interdisciplinary context.

• Subsidized meals
• Partial reimbursement of public transport costs
• Leave: 7 weeks of annual leave + 10 extra days off due to RTT (statutory reduction in working hours) + possibility of exceptional leave (sick children, moving home, etc.)
• Possibility of teleworking (after 6 months of employment) and flexible organization of working hours
• Professional equipment available (videoconferencing, loan of computer equipment, etc.)
• Social, cultural and sports events and activities
• Access to vocational training
• Social security coverage

Gross Salary : 2.788 euros/month