My research presents a strong multidisciplinary approach, oriented at the description and understanding of complex biological behaviors, from DNA to organs. A panel of tools and methods are used, with two major paths of study: respiratory diseases and cancer.
Asthma
In asthma, it has been shown for many years that the measurement of the exhaled concentration of nitric oxide (NO) can be used as a proxy for monitoring the disease status. However, its exhaled concentration is not straightforwardly related to its concentration in the lungs. From these observations, several modelling approaches have emerged to complement the clinical measurements.
Our approach for studying the dynamics of NO has been constructed following a phenomenological point of view. A new model of its dynamics in the lungs has been developed, and presented in a comprehensive work in Frontiers in Physiology. When compared to previous ones, the model presents multiple new features that allow for a better description of this dynamics, especially in the case of asthma exacerbation, characterized by the presence of mucus obstructions and bronchoconstriction.
From this model, the role of NO as a general marker of the bronchi caliber has been suggested, in addition to its role in the asthma monitoring. Our hypotheses, supported by modelling results and analysis of experimental measurements, have been presented in multidisciplinary paper published in the Journal of Applied Physiology, at the interface between clinical studies and mathematical modelling.
Bronchial mucus and associated pathologies
In cystic fibrosis, which is a disease of the bronchial mucus layer, pieces of evidence show that the water content of the mucus is linked to the severity of the symptoms of the disease. However, the link between the disease and the alterations of the mucus content and dynamics is far from being understood.
Regarding the dynamics of the mucus layer in the lungs, a new analysis of the control of the mucus balance in the bronchial region of the lungs has been developed. Our approach is based on the combination of a balance equation for the mucus in an airway and a computational tool characterizing the evaporation of the mucus in the bronchial region. We show that this approach allows for new insights into the dynamics of the bronchial mucus and, more specifically, on the mechanisms controlling the amount of mucus in an airway. The results, presented in an extensive article published in PLoS One, are analyzed in order to bring interesting new perspectives for the understanding and the treatment of mucus pulmonary diseases, such as cystic fibrosis or exercise-induced asthma.
The physics of the bronchial mucus layer is complex. Mucus can be characterized as a non-Newtonian fluid whose properties, namely from a rheological point of view, present a high level of complexity. One model for approaching its rheology consists in describing the mucus as a Bingham fluid, or threshold fluid. Under a certain level of shear stresses, the fluid behaves as a solid, then adopts a fluid behavior at high shear stresses. This assumption allows to study in details the mechanics of mucus, namely its displacements and interactions with the tissues and the airflow. In our pre-published work, we describe the curvature-induced mucus motion that appear at bifurcations in the bronchial tree, based on a comprehensive mathematical approach that takes advantage of lubrication approximation.
Evaporation in the bronchi
As the bronchial mucus is at the interface between the pulmonary tissues and the external air environment, it is submitted to intense heat and mass transfers between the two compartments, namely through cycles of evaporation during inspiration and condensation during expiration.
Based on our previous models, this complex behavior has been analyzed in a cohort of athletes performing experimental endurance tests. Ventilation and blood parameters were sampled during the experiment, suggesting that the level of epithelial damage observed after intense exercise is linked probably to the ventilation rate and the room air conditions in temperature and humidity. These hypotheses have been verified using an adapted version of our previous mucus model, which confirms that intense exercise in dry and cold air conditions can lead to bronchial epithelial damage, probably through mucus dehydration. See our recently published article in the Journal of Applied Physiology.
Previous work from colleagues Noël and Mauroy studied the context of ventilation optimization in the respiratory system. Based on the minimization of the work needed for optimal gas exchange that would ensure body requirements, they demonstrated that the frequency and amplitude of ventilation is constantly adapted to the body's activity and metabolism regime. Then, we extended this human model to the whole class of mammals and proposed, in a published article in the Peer Community Journal, new allometric relationships for the ventilation parameters coherent with the previously established literature.
As a proof of concept, we extended our model of heat and water transfers in the bronchi to the whole mammalian class, based on body mass variations and related allometric laws for lung geometry and physiology. Our recent article, published in Scientific Reports, unveils some relations between the body mass of the mammal and the heat and water balance of the respiratory system. Namely, the dissipated power during ventilation due to heat and water transfers seems to follow an allometric relationship.
Somatic mutations and DNA ionization potential
Recent progresses in bioinformatic analyses of large datasets of genomic mutations tend to indicate that, among DNA mutations, single base substitutions (SBS) that sometimes induce pathogenic effects present a non-random degree of occurrence, with an influence of the flanking sequences. The presence of electron hole transport along the DNA strains has been suggested as one of the mechanism that could be related to the specificity of base mutability.
In a recent paper, my colleagues Pucci & Rooman analyzed the correlation between the frequency of occurrence of SBS in the Single Nucleotide Polymorphism Database (dbSNP) with the value of the ionization potential in the nucleotidic context of these mutations. They observed a significant anticorrelation between these two quantities, meaning that a lower value of the ionization potential indicates a higher probability of substitution.
The study of this role of electron-hole transport in the mutagenicity is still ongoing, with an exploration of a larger set of databases, namely somatic mutations in cancer or methylome. I presented the current outputs of this work at the European Conference on Computational Biology (ECCB 2022) in Sitges, Spain (see Publications section).
Organ development
In collaboration with Dr. Stephan Clavel from Université Côte d'Azur, we studied the mechanisms of the early stages of developement of prostate organoids. These cellular models are of high interest, as they recapitulate quite well the histology and functions of the future mature organ. We gained new insights from an ad-hoc mathematical model of growth and specialization of the organoid, based on reaction-diffusion theory. This ongoing research project has been presented at the 2021 Endocrine Abstract Conference.