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Physiopathological roles of the Prokineticins (PROK) in the lung barrier (LB)

Published on 24 April 2024
Head of the project   
     Mohamed Benharouga, Ph.D, HDR

Research project
The lung epithelium (LE) is an important physical barrier, which acts as a shield against airborne toxins, pollutants and foreign pathogens, such as bacteria and viruses. The LE responds to harmful stimuli by releasing soluble pro-inflammatory and pro-angiogenic factors that are involved in the inflammation and neo-vascularization responses, necessary processes for the recruitment of the innate immune system cells, such as neutrophils. Indeed, during a physical, chemical or infection assault (bacteria or virus), lung epithelial cells send signals to the endothelium to initiate neutrophils recruitment. These cells are recruited to the site of injury through trans-endothelial and trans-epithelial migration (TTM) involving a series of ligand-receptor interactions. In the airway diseases that are characterized by chronic inflammation and lung neo-vascularization, such as cystic fibrosis (CF), COVID infection and lung cancer, persistent neutrophilic infiltration in the lungs may cause tissue damage through the uncontrolled action of released cytotoxins. Hence, if we manage to control the pathological TTM cascade, we can potentially limit the exacerbation of the airway inflammation, allowing lung healing.
The TTM is a highly regulated process that requires a fine epithelial-endothelial crosstalk that mainly relays on the junctional complexes (JC), which stability is sensitive to a variety of pro-inflammatory and pro-angiogenic mediators.
During the last 15 years, my research group shed light on the role of the prokineticins family members in the control of angiogenic and inflammatory processes in relation to different human diseases, such choriocarcinoma, IUGR, preeclampsia, and recently cystic fibrosis.
Prokineticin (PROK) family includes two canonical soluble ligands; PROK1 also known as EG-VEGF (Endocrine Gland derived-Vascular Endothelial Growth Factor) and PROK2, and their GPCR receptors, PROKR1 and PROKR2 that are directly involved in the control of inflammation and angiogenesis.
Recently, we identified the cellular prion protein (PrPC) as a central junctional protein involved in the protection of the lung epithelial junctional barrier. In parallel, we identified EG-VEGF as a key molecule involved in the destabilization of both endothelial and epithelial barriers.

Considering these original findings, my research group aims at characterizing the role of EG-VEGF/PrPC in association with CFTR (Cystic Fibrosis Transmembrane Regulator) protein, a chloride channel involved in CF, in the process of neutrophils transmigration in order to propose targeted therapies of the circulating ligand EG-VEGF, which may allow decreasing neutrophils infiltration in altered lung epithelium.

The implementation of my research project involves three approaches:
- A clinical approach that is conducted in tight collaboration with Grenoble-University Hospital
- An in vitro/ex vivo approaches that employ 2D and 3D lung and endothelial culture systems.
- An in vivo approach that involves different mouse models related to PrPC, EG-VEGF and CFTR proteins.

The following non-exhaustive list of technologies are employed:
- Molecular Biology: PCR, RT-qPCR, RNAseq
- Cell culture: single culture, co-culture, spheroid, organoid
- Cell Biology: TEER, proliferation, migration, chemotaxis, invasion, Cell surface labelling, ELISA test, tissue and cell imaging, cell surface-ELISA, IP-1 test
- Biochemical: IP, cell surface biotinylation, Western Blot

Project summary

PhD Student involved in the project:

Camille Lyko
Targeting of EG-VEGF protein through structural drug-designed screening to inhibit its proangiogenic and proinflammatory effects in inflammatory diseases.