Using an advanced 'airway on a chip' model for studying the effects of exposome on lung tissue

The project is part of a Nexus project implying 3 partners and 3 PhD students. Partner D1 (John De Vos’ Lab) is expert in iPS cells and their differentiation into bronchial epithelium, Partner D2 (Gladys Massiera) is biophysicists experts in mucus rheology, cilia beating and microfluidics, and Partner D3 (Delphine Muriaux) is virologist expert in human viruses. The PhD students will work jointly to combine expertise and promote transdisciplinarity.
Context : The lungs, a vital organ, are constantly exposed to a multitude of environmental factors, collectively referred to as the exposome. It is not surprising that respiratory diseases such as COVID-19, chronic obstructive pulmonary disease (COPD), and asthma, are major public health concerns. However, the interactions between these exposures are complex and not yet fully understood due to the lack of a realistic in vitro model that mimics the complex structure of the airways. Organoids, which recapitulate normal tissues, offer a promising platform for studying the effects of the exposome on lung tissue. Our team has already developed a robust human induced pluripotent stem cells (iPSC)-derived bronchial epithelium at air/liquid interface model called iALI. 
Proposed objectives and methods : The PhD project will comprise two complementary research axes that address a common biological question - the interplay between environmental pollutants and respiratory viral infections in driving airway epithelial dysfunction - while leveraging overlapping experimental approaches and analytical tools. Together, these studies will provide mechanistic insights into how the exposome shapes respiratory health and disease.
•    Evaluate, by quantitative application of air pollution, in combination with viral infections, the impact of the exposome on bronchial epithelium (iALI) using an array of high-precision tools such as proteomics (Olink) and single-cell sequencing. The synergistic effects of pollutants and viral infections will be assessed, and the functional basis of the harm caused by the exposome will be investigated by interfering with the signaling pathways affected.
•    Establish an inducible protein degradation (degron) system through CRISPR/Cas9-mediated tagging of the endogenous SCGB1A1/CC10 locus in one normal iPS cell line. This approach will enable functional investigation of SCGB1A1, a key epithelial protective factor involved in responses to both environmental pollutants and respiratory viral infections. Using this model, we will determine the contribution of SCGB1A1 to epithelial resilience, inflammatory responses, and tissue repair following combined exposure to air pollutants and influenza virus. The consequences of SCGB1A1 depletion or modulation will be characterized at single-cell resolution using scRNA-seq, allowing identification of cell type-specific responses, altered signaling pathways, and molecular mechanisms underlying susceptibility to dual environmental and infectious insults.
Expected results : Expected outcomes include identification of molecular mechanisms underlying pollutant-virus interactions, characterization of SCGB1A1-mediated epithelial protection, discovery of novel therapeutic targets and biomarkers, and generation of advanced human airway models for exposome research.
Feasibility : The project benefits from a high level of feasibility, supported by the consortium’s established expertise in iPSC culture and differentiation, CRISPR/Cas9 genome engineering, and advanced analytical approaches including single-cell transcriptomics. Its successful implementation is further strengthened by the strong complementarity of the three partners, who contribute specialized expertise in stem cell biology, microfluidics, and virology, respectively. In addition, the project is embedded within a broader Nexus initiative involving two other PhD students specializing in virology and biophysics. The recruited doctoral candidate will therefore evolve within a highly interdisciplinary environment and will closely interact with these complementary projects, fostering scientific synergies and enhancing the overall impact of the research program.
 

Le laboratoire de Physiologie et médecine expérimentale du cœur et des muscles PhyMedExp, est une unité mixte de recherche (INSERM, CNRS, Université de Montpellier) créée le 1 janvier 2011. C’est une unité pluridisciplinaire fédéré autour de la physiologie et physiopathologie des tissus contractiles (muscles cardiaques, lisses et striés), et de leurs interactions avec leur environnement. Il rassemble plus de 150 personnes sur 6 équipes et développe une stratégie de recherche allant des structures élémentaires (gènes et molécules), à l’organisme entier, en passant par les cellules et les tissus.

Les principaux objectifs de l’unité sont d’identifier par une approche intégrative , les mécanismes moléculaires associés à la fonction musculaire en condition normale ou pathologique (cardiovasculaire, héréditaire , maladies musculaires acquises et iatrogènes, respiratoires, digestives).

Le véritable atout de PhyMedExp est d’allier recherche fondamentale et recherche translationnelle au service du patient, un défi facilité par son implantation sur le site de le CHRU Arnaud de Villeneuve de Montpellier, et l’interaction dans chaque équipe de chercheurs fondamentaux avec les chercheurs cliniciens et leurs services cliniques associés.

L'étudiant réalisera sa thèse dans l'équipe de Arnaud Bourdin, sous la direction de John De Vos

Niveau Master requis.

Expérience en culture cellulaire recommandée.

Formation voire expérience en bioinformatique souhaitée.

Une expérience en virologie est un plus.