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Phd student (M/F) : Enzymatic kinetics of extracellular matrix remodeling: analytical and biophysical characterizations of synthetic models

This offer is available in the following languages:
Français - Anglais

Date Limite Candidature : mercredi 3 novembre 2021

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General information

Reference : UPR4301-MARPER-061
Workplace : ORLEANS
Date of publication : Wednesday, October 13, 2021
Scientific Responsible name : Prof. Josef Hamacek, Prof. Anand Yethiraj
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 December 2021
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly

Description of the thesis topic

The proposed thesis is part of the X-CROWD project funded by the ANR, which aims at studying the enzymatic remodeling of the extracellular matrix (ECM). The work carried out by the recruited PhD student will focus primarily on kinetic studies of the main metalloenzymes in the presence of monodisperse crowders and binary mixtures with different partial molar fractions of crowders of two different sizes. These controlled conditions will allow us to gather information on the effect of the relative enzyme/obstacle size, which is important to address the more complex situations where the crowder size evolves with the reaction time. The PhD student will have to simultaneously characterize these crowded media (DLS, rheological properties) and their interactions with substrates/enzymes (PFG-NMR). The latter experiments will be conducted in Canada at Memorial University of Newfoundland (MUN) in collaboration with prof. Anand Yethiraj's soft materials lab, in the framework of an international co-tutelle of this thesis between the University of Orléans and MUN. Furthermore, these studies will focus on model substrates of limited size in order to identify the effect of the artificial matrix. For example, pure hyaluronic acid (HA) oligomers (octamers, decamers) from commercial sources will be used as substrates to probe the kinetics of hyaluronidase. The kinetics will be followed by spectrophotometry (neocuproin and/or Morgan-Elson assays, turbidimetry). Speciation during the kinetics that are most impacted by crowding will be probed with capillary electrophoresis and/or mass spectrometry. Fluorogenic peptide substrates will be used for example in the case of collagenases and/or elastases. These specific substrates allow the recovery of fluorescence after cleavage without the need to separate the products. In addition, the inhibition mechanism of these enzymes in crowded environments will also be studied. Kinetic models will be developed by the X-CROWD theory team to rationalize the experimental results obtained. This work will then be extended to natural substrates in order to consolidate the theoretical simulations of extracellular matrix remodeling.

Work Context

The PhD student will work within the thematic group “Molecular assemblies and complex systems” at the Center for Molecular Biophysics (CBM - UPR4301) located in Orléans on the CNRS campus. The CBM is developing research at the interface of Chemistry, Biology and Physics with the main interest in the molecular mechanisms of living organisms and the dysfunctions that lead to the development of certain diseases. The student will benefit from the infrastructures and equipment of the CBM.
The thesis is funded by an ANR program. The doctoral student will be supervised at CBM by prof. Josef Hamacek within his research group. An international co-supervision will be established between CBM / University of Orléans and Memorial University of Newfoundland (in the soft materials lab of Anand Yethiraj, St. John's, Canada), where the PhD student will carry out the PFG-NMR experiments. The doctoral student will be led to interact substantially with the other partners of the project.

Additional Information

The candidate should have good oral and written communication skills in English. We are looking for a motivated and curious student who will be able to fully invest in his project.
Candidates must send their CV and cover letter via the emploi.cnrs.fr website.
In addition, the candidate should provide a one-page summary of the master's thesis in French and English, at least one reference (person likely to be contacted), and M2 grades.
Only applications received via this CNRS procedure will be considered.

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