MucoReaDy

The objective of project MucoReaDy is to study the alteration of the mechanism of mucolilicary clearance for the pathology of Cystic Fibrosis (CF) and Allergic Broncho-Pulmonary Aspergillosis (ABPA), in a mucus dynamics perspective. In these pathologies, the pulmonary dysfunction progressively worsens over time, leading to a decline in percent predicted forced expiratory volume in 1s (ppFEV1), heralding advanced lung disease that is often irreversible. Newborn screening has enabled early initiation of standard-of-care therapies in children with cystic fibrosis, leading to improvements in measures of growth, nutrition, and lung disease. Yet premature mortality remains, with a median predicted survival of 47 years. The perspective considered in this project is to get an accurate understanding of the mechanisms involved in the mucus production, maturation, self-stratification and above all its motion induced by its interactions with its complex and mobile surrounding. In order to explore this topic, our strategy is to build a synergy between mathematics and simulation (LMAP, UMR CNRS 5142), medicine and hospital therapy (CHU Bordeaux and CHU Toulouse) for both adult medicine and pediatrics, soft matter physics and chemistry (IPREM, UMR CNRS 5254). The questions we address in order to investigate this problem are, among many: How the different states of mucus maturation impact its rheology? Depending on its environment, is it possible to predict the functionality of the mucus by modeling (mathematical model and simulation). That is to say, is it able to be put in motion by the vibrating epithelium given this strongly spatially variable rheology? Given this quantification of mucus mobility, is it possible to build a predictive cartography that will take into account only a few rheological parameters in order to exhibit the evolution of mucociliary clearance? Especially in the context of cystic fibrosis pathology and its therapy? Can the methodology be sufficiently robust to estimate the risk of a resistance to drug therapy or not? Considering multi-component chain-growth reactive models, can we explain the characteristic times of aspergillosis evolution? can we explain its resistance to anti-fungal therapy? Such outcome would help to clarify the protocol between corticoid/antifungal therapy for ABPA. The project is organized in 4 main tasks, the first one being dedicated to coordination. The Task 2 will focus on advanced modeling and numerical simulation of lung epithelium environment, involving the lowest possible number of parameters: We will introduce the mathematical modeling of the system CFTR/transcystosis, elastic cilia, goblet cells, mucins, mucus maturation, pus/bacterial activity, air/lumen. At a clinical level, the project MucoReaDy wants to prove that this cheap and fast diagnostic can be used to check the efficiency of a therapy is on the patient, in only a few weeks instead of 3-6 months, the typical current clinical time scale. These aspects concern the Task 3. Indeed, our goal is to verify if the evolution of rheology fits the evolution of the patient's clinical indicators (exacerbation level, mutation, age, infection strength and type, VEMS, sputum volume, etc...), in order to identify the soonest possible any resistance to the therapy. The urgent target is the next-generation corrector for CF, the triple-therapy (Trikafta) Elexacaftor-tezacaftor-ivacaftor, available in 2020 for 12+ year old people. Another main novelty of project MucoReaDy will be the modeling of agent proliferation and their mobility in this environment, dealt with in the Task 4. The goal is to get growth factors, transport velocity and diffusion/dispersion at the cell level, in the perspective of injecting them in upscaled models. This will be applied to fungal and bacterial proliferation, focused on ABPA and possibly applied to Pseudomonas Aeruginosa and Burkholderia cepacia complex.