The tight regulation of platelets production and function is a key to prevent bleeding and thrombotic disorders that have a high impact on morbidity. We have developed a program based on the combination of biochemistry, genetic and high resolution imaging to link molecular mechanisms to medical questions in the field of hemostasis and thrombosis. Our team has a strong experience in the biology of phosphoinositides (PIs), which are spatio-temporal regulators of major signaling pathways, of their metabolizing enzymes (kinases/phosphatases, phospholipases) and effectors (GTPases, tyrosine and serine/threonine kinases for examples). In this context, our research focuses on:
- Understanding how PIs, their regulators and effectors control fundamental mechanisms of cell biology. One of our aims is to understand the role of these lipids in the control of cytoskeleton/membrane dynamics in platelet production (megakaryocyte differentiation). This encompasses studying the relationships with the extracellular matrix, cytokines and endothelial cells, as well as their role in membranes physical properties, migration and receptor activation/fate.
- Investigate the molecular mechanisms of platelet production and functions focusing on the role of class I, II and III PI3-kinases in genetically modified mice models or by using pharmacological inhibitors to differentiate between specific functions that can be targeted in therapy and redundancies.
- Linking molecular mechanisms to medical questions through the integration of clinicians from the Rangueil Hospital to our team. Conditions such as inflammatory response (sepsis, stroke) or risk associated to antiplatelet drugs in interventional cardiology are examples of our projects. Close interaction with the 'Centre de Référence des pathologies plaquettaires' (CRPP) gives us access to patients with constitutional thrombocytopenia and inherited platelet disorders linked to bleeding diathesis. The impact of new targeted drugs on platelet functions and the bleeding risk is also investigated with the department of hematology-oncology. We globally aim at uncovering markers to monitor antithrombotic therapies, risk for acute ischemic events, new targets and therapeutic strategies.
Expected health effects
Better knowledge of the molecular mechanisms of normal and
pathologic hematopoietic cell responses should give insights into the diagnosis
and the treatment of thrombocytopenia, thrombosis and pathologies linked to a
dysfunction in platelet production and functions. This includes bona fide haemostasis defects but also bleeding disorders/ thrombosis secondary to an unrelated therapeutic intervention such as cardiovascular surgeries or tumoral chemotherapies.
Hematopoietic stem cells differentiation
Primary culture of megakaryocytes (mouse, human)
Cell lines (fibroblasts, epithelial, tumoral, megakaryoblasts, tetracyclin inducible cell lines…)
Transgenic mice models
Patients’ cells and samples
- classical protein biochemistry and molecular biology, cell culture, lentiviral production and transduction, recombinant protein production
- Megakaryocyte differentiation in vitro from bone marrow or fetal liver hematopoietic progenitors
- Techniques to monitor platelet functions ex-vivo and in-vivo (aggregation, secretion, ex-vivo thrombosis under blood flow conditions by microfluidic and ultrafast imaging, in vivo thrombosis models (carotid injury), stroke models)
- phosphoinositides and lipids biochemistry and quantification (lipidomics, mass assay, HPLC)
- Videomicroscopy, sensitive spectral confocal imaging, super resolution imaging, FRET, FRAP, 3D confocal analysis of tissues and migrating cells