L'équipe de Muriel Laffargue (UMR1048, Toulouse) recherche deux post-doctorants pour étudier les mécanismes cellulaires et moléculaires impliqués dans la dégradation et la dysfonction de la paroi vasculaire au cours de l'athérosclérose. Les deux projets proposent d'approfondir nos connaissances quant à l'influence des phénomènes de transduction des signaux mécaniques et de l'inflammation dans ce processus pathologique:
2 POST-DOCTORAL POSITIONS
EARLY AND LATE ATHROSCLEROSIS
Starting date: from october 1st 2018
Funding: 18 months for each proposition
Research group: Team M Laffargue Team 5 "HDL and PI3K Signaling in Atherosclerosis"
Workplace: Inserm UMR1048, Toulouse, France
Skill area: early and late atherosclerosis
Salary: the salary will follow the guidelines of the Inserm status, depending on experience
Our research projects aim to identify molecular and cellular mechanisms involved in early and late atherosclerosis to propose novel therapeutic pathway to prevent and/or treat arterial damages. In this context, we propose two post-doctoral positions.
Context of the laboratory: The host team belongs to the I2MC (http://www.i2mc.inserm.fr/index.php/fr/). It provides an excellent environment to perform state-of-the-art in cardiovascular research.
Endothelial dysfunction represents a key step in the initiation of atherosclerosis, a complex and multifactorial pathology that accounts for a significant part of cardiovascular disease. Atherosclerosis develops first in a pattern that correlates with low shear stress localized with branches and curvatures of the arterial tree. However, the mechanisms that participate to endothelial dysfunction in atheroprone territories are not fully understood. Very interestingly, endothelial cells are able to convert shear stress into biochemical signal to control cellular functions. This mechanical stimulus is detected by mechanosensors in endothelial cells leading to the maintenance of vascular homeostasis. This project focus on mechanosensors and associated signaling pathways activated downstream shear stress to identify a new important actor for endothelial functions and investigate its role in the arterial wall during atherosclerosis development.
Focus and specific objectives:
Using a fluidic unit designed to mimics artery shear stress in a fluid flow chamber, we will particularly identify molecular mechanisms activated downstream shear stress forces and their consequences on endothelial phenotype. The role of the identified mechanisms on endothelial function during arterial disease should be validated by using an established murine model susceptible to atherosclerosis. Thus, combining original in vivo and in vitro models with molecular and cellular approaches (e.g., western-blot, immunofluorescence, immunohistochemistry, pcr, …), the successful candidate will determine new cellular and molecular events that control endothelial function in the specific atheroma-prone regions of the artery.
Specific tools: The host team has established the tools (siRNA and genetically-modified mouse model) to modulate mechanosensor expression in endothelial cells in vivo and in vitro. The candidate will be in charge to develop the fluid flow chamber system. Collaborations with Institut Necker (Team E. Morel, INEM, Paris) previously established will help to optimize the in vitro approach.
Applicant Profile: The applicant must have a PhD in cellular biology or physiopathology. Prior knowledge and research experience in cell biology is mandatory. A documented positive experience in studying endothelial cell and/or shear stress will be an asset. The applicant will be used to practice experiences with transgenic mice model and handling microsurgery procedures would be beneficial.
The applicant should be highly motivated, with excellent communication skills and should demonstrate rigor and initiative. Moreover, team spirit is essential and professional mobility is required to perform some experiments in Paris with our collaborators in Institut Necker.
Chronic Inflammation of the arterial wall induced by mechanical and lipid stress leads to progression of atherosclerosis and culminate with plaque rupture at the end stage of the pathology. The increased pro-inflammatory environment induces a significant change in elastic fibers, that are responsible for tissue elasticity. Elastin is the protein presenting the longest halflife of the human organism (70 years) and exhibits almost no turn-over during life, suffering an inexorable degradation. So, during atherosclerosis, but also after treatment by angioplasty where neoatherosclerosis could occur, an intense elastolysis is observed, leading to increased vascular stiffness but also to the production of elastin-derived peptides (EDPs). The generated peptides, also called elastin peptides or elastokines, are not inert and actively participate in the development of the inflammatory processes of the pathology. We were the first to demonstrate, using mouse models of atherosclerosis, that these peptides were responsible for a drastic increase in atherosclerosis development through the elastin receptor complex (ERC). Based on these results, we now propose to evaluate novel therapeutic strategies aiming to prevent biological responses induced by the elastin peptides.
Focus and specific objectives:
Using different mice model of arterial diseases, we will evaluate the therapeutic potential of different inhibitors of ERC activation. Peptide interference strategy as well as chemical inhibitors will be evaluated. Impacts of both strategies on atherosclerosis plaque size, inflammatory infiltrate, foam cells and TF plaque content will be evaluated. In parallel, an in vitro study on immune and vascular cells will permit to validate specific effect of different inhibitors.
Specific tools: This project benefit rom close collaboration with the team of Laurent Duca (Laboratoire SiRma, Reims) in Reims who has established the tools to modulate ERC response to elastin peptides.
Applicant Profile: The applicant must have a PhD in cellular biology or physiopathology. Prior knowledge and research experience in vascular pathology is required. The applicant will be used to practice experiences with mice model and handling microsurgery procedures would be beneficial.
The applicant should be highly motivated, with excellent communication skills and should demonstrate rigor and initiative.
Contact: Please send by email a full CV with a brief summary of professional experience and a short statement of research interests. Applicant should also email the names and contacts of 2 referees, and a motivation letter to Dr. Muriel Laffargue: