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Reference : UMR5129-MARCLO-041
Workplace : GRENOBLE
Date of publication : Friday, June 11, 2021
Type of Contract : FTC Scientist
Contract Period : 18 months
Expected date of employment : 1 September 2021
Proportion of work : Full time
Remuneration : Between 2648,79 et 2897,29 € gross monthly
Desired level of education : PhD
Experience required : Indifferent
It is now extensively documented that animal cells sense the mechanical properties of their environment. But in vitro assays are still performed on plastic or glass Petri dishes, which are known to induce drifts in genetic expression . Growing cells on a soft matrix that mimics the mechanical properties of the tissue aims at increasing the physiology of the assays in order to get more relevant observations regarding their application for human health. This strategy is recognized as one of the critical steps for building disease-relevant models for drug discovery . In this context, our group has developed soft synthetic matrices for 2D cell culture with robust mechanical and surface properties .
Here we focus on the design of mechano-mimetic supports for lung tissues. Lung epithelia have a complex stratification that originates from the interface of the tissue with air. This complexity is addressed by air/liquid interface (ALI) inserts that have been proposed for in vitro reconstruction of the bronchial epithelia. ALI system was shown to overcome several artefacts coming from the difference in anatomy, cellular composition and molecular responses between humans and rodents . ALI shares similar objective as 3D organoids, with simpler imaging capabilities. However, this technique shows limitations in the reconstruction of tumor tissues. A pitfall could be that the ALI membrane is stiff and it may consequently induce a drift of cell phenotypes and prevent their reconstruction. Thus our objective is to set up Air/Liquid interface inserts with a soft permeable membrane, betting that this improvement will increase the potentialities of this technique and makes it more versatile. This development is performed in the context of lung adenocarcinoma, a leading cause of cancer deaths (5 years survival rate: 17%). A specific subtype of adenocarcinoma, the KRAS-mutated tumors often found in nonsmoking patients, remains a challenge for therapeutic molecules, raising the question of the accuracy of drug screening in preclinical phase. Our group is presently characterizing the mechanical properties of this pathological tissue.
The project thus addresses the development of a permeable soft membrane for ALI inserts. The mechanical properties of the membrane must be in the range of 1-10kPa and must be easily tunable, while it must stand as an insert. To this end, we anticipate the use of photochemistry and double network hydrogels . 3D printing technologies can be envisioned. The candidate will have to set up a process to reach this goal. He/she will be shared between two labs, the LTM, that hosts expertise in photolithography and 3D printing, and the CERMAV, with a strong expertise in polymer chemistry and photopolymerization.
- design of a hydrogel with tunable rigidity and controlled permeability consistent with the mechanical properties of animal tissues, compatible with the diffusion of culture medium and compatible with bioassays.
- characterization of the mechanical properties and the permeability of the hydrogel
- design of the whole ALI soft insert.
- Basic skills : Polymer chemistry. Rheology.
- Operationnal know-how: Design of polymers. Rheometry. Additional knowledge in photochemistry will be appreciated. Basics in cell biology are a plus.
- Social skills : The candidate must feel comfortable in working in two labs with a joint supervision, and to be part of interdisciplinary teams (chemistry, biophysics, technology, physics).
- English spoken and written
The LTM is a joint CNRS/University of Grenoble Alpes research unit, with 2 teams and a staff of about 90. The laboratory is located on the CEA-LETI site in Grenoble. The candidate will join the Micro and Nanotechnologies for Health, Energy and Environment (MiNaSEE) team.
This project is part of a larger project, funded by the CLARA (Canceropole Lyon Auvergne Rhône Alpes) which involves 4 partners (A. Nicolas, LTM; C. Chaveroux, CRCL; L. Chalabreysse, HCL; C. Migdal, Cell&Soft). This part of the project benefits from the collaboration with R. Auzely-Velty, CERMAV.
Constraints and risks
The LTM is located in Grenoble Presqu'île (Minatec campus) and the CERMAV is located in the campus of the university. Both are connected by public transportation (30min). The candidate will share his/her time between both labs.
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