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Reference : UMR7275-GUIDRI-001
Workplace : VALBONNE
Date of publication : Saturday, February 01, 2020
Scientific Responsible name : Dr. Guillaume DRIN
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 July 2020
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
Toxoplasmosis is a parasitic infection whose causative agent is the protozoan Toxoplasma gondii. The distribution of the disease is worldwide with a prevalence varying from country to country (from 7 to 80%). The infection is benign, even asymptomatic in the vast majority of cases. Nevertheless, it presents a very serious risk for pregnant women (the fetus is at risk of developing neurological sequelae and eye damage) and immunocompromised people (severe brain damage, eye inflammation), sometimes with a life-threatening prognosis.
T. gondii is an obligate parasite; this means that it must reside in the host cell to survive. To this end, it injects into the host cell a set of effector proteins that are contained in secretory compartments called rhoptries and micronemes. Once inside the host cell, these effectors hijack various subcellular processes that allow the parasite to enter, replicate and persist in the cell.
The aim of the thesis is to improve our knowledge, quite rudimentary, of the molecular mechanisms responsible for the biogenesis of the secretory compartments of T. Gondii. In particular, one goal is to study a new multidomain protein called TgREMIND which appears to play a key role in the formation of these compartments. Indeed, it would act upstream at critical stages of vesicular trafficking between the Golgi apparatus and recycling endosomes. It is more than likely that this protein associates with the surface of these membrane compartments and interacts with key proteins of vesicular trafficking, the small G protein called Rab
During the thesis an aim will be, among others, to purify and label with fluorescent moieties the TgREMIND protein as well as these different isolated structural domains in order to determine, by in vitro functional and spectrofluorometric approaches, its mode of action. In particular, we aim to analyze whether it can specifically associate with the membranes of the Golgi apparatus or the endosomes in T. gondii. The phD student will also investigate whether TgRemind has the ability to remodel membranes by confocal and electron microscopy. In parallel, he/she will study whether TgREMIND is a GDP/GTP exchange factor that can activate certain Rab proteins involved in vesicular trafficking. Then, the study will be generalized to homologous proteins in T. Gondii and other parasites.
The obtained outcomes will allow to better understand the particular role of TgREMIND in the genesis of T. gondii secretion compartments and thus its importance for the virulence of the parasite. In the medium term, such a study could be useful in the development of novel therapeutic strategies by guiding the design of new antiprotozoal agents targeting TgREMIND.
Our research team is based at the Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) which houses more than 200 biology researchers at the heart of the Sophia-Antipolis campus (French Riviera), one of the most dynamic technology parks in Europe. The institute is a joint unit between the CNRS, one of the world's leading research institutions, and the Université Côte d'Azur.
Our research team is internationally known for its work on the molecular mechanisms of lipid transport in the eukaryotic cell (publication in Science, Nature Communications, EMBO J.,...). We also have extensive expertise on vesicular transport processes. In general we have a major interest in describing protein-membrane, protein-protein and protein-ligand interactions and their role in certain cellular functions.
The thesis project is at the interface between cell biology and structural biochemistry. It is part of a project, funded by the French National Research Agency (ANR) , that associates our team with that of Dr. Stanislas Tomavo (biology of T. Gondii) and that of Dr. Sophie Zinn-Justin (structural study) at the Institut de Biologie Intégrative de la Cellule in Gif-sur-Yvette, near Paris.
The thesis student will be attached to the Doctoral School 85 which regroups all the research teams working in the field of Life Sciences and Health in the Nice/Sophia-Antipolis region.
The student will be supervised by Dr. Guillaume Drin, Research Director at the CNRS, who is an expert in lipid/protein interaction, spectroscopy, biochemistry and cell biology. He was awarded the CNRS Bronze Medal in 2010.
1. Lipp N.-F., Gautier R., Magdeleine M., Renard M., Albanèse V., Čopič A., Drin G*. An electrostatic switching mechanism to control the lipid transfer activity of Osh6p (2019) Nature Communications 10, 3926.
2. Wilhelm L.P., Wendling C., Vedie B., Kobayashi T., Chenard M.P., Tomasetto C., Drin G., Alpy F. STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites (2017) EMBO J 36, 1412-1433.
3. Moser von Filseck J., Vanni S., Mesmin B., Antonny B., Drin G.* A phosphatidylinositol-4-phosphate powered exchange mechanism to create a lipid gradient between membranes (2015) Nature Communications 6, 6671.
4. Moser von Filseck J., Copic A., Delfosse V., Vanni S., Jackson C.L., Bourguet W., Drin G.* INTRACELLULAR TRANSPORT. Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate (2015) Science 349, 432-6.
Constraints and risks
In vitro biochemistry and fluorescence microscopy experiments. Work on recombinant protein only. No handling of pathogenic organisms, human tissues and radioactive products.
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