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Unit Programme - Molecular Mechanisms of Airway Protection

Dr Vito Mennella 

The main aim of the research program is to understand how the airways respond, adapt and survive when confronted with different types of insults such as toxic particulates and drugs that target the airways.

The airways play a central role in protecting our health throughout the life course. The most recent systematic analysis of the global burden of disease, which includes data from more than 200 nations, has shown that the largest increase in risk of disease results from airway exposure to pollution from ambient particulate matter (PM). It is therefore of the outmost importance that we investigate the molecular mechanisms driving induction and progression of toxicity in the airways in order to identify biomarkers of disease and rescue strategies.

Toward this goal we employ airway primary cellular models from different lung compartments to understand how different molecular insults affect pathways linked to airway defence such as mucociliary clearance, oxidation pathway and immune response. Our plan is to develop an airway specific toolbox combining unbiased high-throughput assays and mechanistic studies to systematically identify key molecular events, common or different, in the adverse outcome pathways driven by potential toxicants. We employ a range of molecular tools including CRISPR-Cas9 loss of function studies, proximity mapping protein-protein interaction analysis and advanced imaging technologies such as super-resolution microscopy and volumetric EM to provide both a global and detailed view of airway cellular phenotypes.

In regard to public health impact, environmental pollutants will be a primary area of focus since adverse health effects, including cardiovascular effects and respiratory symptoms and exacerbations, have been clearly linked to short and long-term exposure to PM2.5 and PM10. The health risks of pollution are especially high for patients affected by chronic obstructive pulmonary disease (COPD), asthma and children, leading to an increase in premature deaths. Moreover, we will focus on how patients are affected by rare diseases of the lungs such as motile ciliopathies, since they can be at risk population.

Our knowledge and tools will be shared with the scientific community and industry partners for use in analysis of toxicity and adverse outcome pathways of novel compounds used in the clinic or introduced in the environment, such inhaled drugs and their delivery systems, new materials or environmental pollutants.

Selected Publications

  1. Blume C, Jackson C, Spalluto M, Legebeke J, Nazlamova L, Conforti F, Perotin-Collard JM.  Frank M, Crispin M, Coles J, Thompson J, Ridley R, Dean LSN, Loxham M, Azim A, Tariq K, Johnston D., Skipp PJ, Djukanovic R, Baralle D, McCormick C, *Davies E D, *Lucas J, *Wheway G and *Mennella V “A novel isoform of ACE-2 is expressed in human and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection. Nature Genetics. 2021. 53, 205-214.
     
  2. Liu Z, Nguyen QPH, Nanjundappa R, Megherbi A, Delgehyr N, Doherty R., Thompson J., Jackson C., Dell S, Czymmek K, Munier A Mahjoub M and Mennella V “Super-resolution Reveals Novel Cilium in Airway Multiciliated Cells”. Developmental Cell. 2020. 55 (2), 224-236 Preview on Developmental Cell and review on Faculty opinions
     
  3. Nguyen QPH, Liu Z, Zlock L, Coyaud E, Laurent E, Ouyan H, Finkbeiner W, Moraes T, Raught B and Mennella V “Comparative super-resolution map of basal foot in primary and motile cilia” Developmental Cell. 2020. 55 (2), 209-223.
     
  4. Liu Z, Nguyen QPH, Guan Q, Albulescu A, Erdman L, Mahdaviyeh Y, Kang J, Hong O, Hegele R, Moraes T, Dell S, Mennella V,  “Quantitative Super-resolution Toolbox for Diagnosis of Motile Ciliopathies” Science Translational Medicine. 2020 Mar 18; Vol 12 535 eaay0071 Manuscript featured as magazine cover
     
  5. Chioccioli M, Feriani L, Nguyen QPH, Kotar J, Dell S, Mennella V, Amirav I and Cicuta P,  "Quantitative High-Speed Video Microscopy profiling discriminates between variants of PCD caused by DNAH11 and HYDIN mutations, American Journal of Respiratory and Critical Care. 2019 199 (11), 1436-1438
     
  6. Sydor A, Coyaud E, Rovelli C, Liu H, Laurent E, Raught B and Mennella V “PPP1R35 is a novel centrosomal protein that regulates centriole length in concert with Microcephaly Protein RTTN” Elife. 2018. Aug 31;7. doi: 10.7554/eLife.37846.
     
  7. Fishman EL, Jo K, Nguyen QPH, Dong K, Royfman R, Cekic A, Khanal S, Miller A, Simerly C, Schatten G, Loncarek, J, Mennella V, and Avidor-Reiss T  "A novel atypical centrosome in human spermatozoon"  Nature Communications. 2018. 9 (1), 2210
     
  8. Wong KS, Mabanglo MF, Seraphim TV, Mollica A, Mao Y, Rizzolo K, Leung E, Moutaoufik MT, Hoell L, Phanse S, Goodreid J, Barbosa LRS, Ramos CHI, Babu M, Mennella V, Batey RA, Schimmer AD, Houry WA “Acyldepsipeptide analogs dysregulate human mitochondrial ClpP protease activity and cause apoptotic cell death. Cell Chemical Biology. 2018. 25 (8), 1017-1030. e9