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Platelet granule biogenesis: molecular and functional aspects

Research unit

UMR_S 949 - Biologie et pharmacologie des plaquettes sanguines : hémostase, thrombose, transfusion (BPPS)
10, rue Spielmann - BP 36 67065 Strasbourg Cedex

Group

Name: Biologie de la thrombopoièse

Group leader: LANZA François - francois.lanza@efs.sante.fr

Group leader's phone: 0388212525

Website: Visit website

Group organization:
- Chercheurs: 6
- ITA: 5
- Doctorants: 2
- Post-Docs: 1
- Autres: 5

Publications of the team linked to the topic (3 last years):
1) Pertuy F, Eckly A, Weber J, Proamer F, Rinckel JY, Lanza F, Gachet C, Leon C. Myosin IIA is critical for organelle distribution and f-actin organization in megakaryocytes and platelets. Blood 2014; 128:1261-1269
2) Badirou I, Pan J, Souquere S, Legrand C, Pierron G, Wang A, Eckly A, Roy A, Gachet C, Vainchenker W, Chang Y and Leon C. Distinct localizations and roles of non-muscle myosin II during proplatelet formation and platelet release. J Thromb Haemost. 2015; 13: 851-859
3) Pertuy F, Aguilar A, Strassel C, Eckly A, Freund JN, Duluc I, Gachet C, Lanza F and Leon C. Broader expression of the mouse platelet factor 4-cre transgene beyond the megakaryocyte lineage. J Thromb Haemost 2015; 13: 115-125.       

About PhD

PhD Director: LéON Catherine - catherine.leon@efs.sante.fr

Phone: 0388212525

Junior advisor: non

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Platelet granule biogenesis: molecular and functional aspects

Project: Blood platelets play an essential role in normal haemostasis to prevent hemorrhages, but are also directly responsible for arterial thrombosis. Platelet activation is accompanied by the secretion of the content of their alpha granules and dense granules. This step is particularly important since these storage organelles contain proteins and agonists involved both in the activation of platelets and coagulation, but also in angiogenesis and inflammation. In addition, diseases resulting from abnormality of alpha or dense granules are associated with high risk of bleeding.
Despite the importance of platelet granules in various physiological processes, little is known about their biogenesis. Platelet granules belong to a group of lysosome-related organelles (LRO for Lysosome Related Organelles), derived from the endocytic pathway. Besides the platelet granules, this group includes among others the melanosomes, pigmented organelles generated in skin melanocyte and eye cells, and other organelles that regulate pulmonary plasticity or immunity. Some LROs are abnormal in Hermansky-Pudlak syndrome (HPS), a group of rare disorders characterized by partial albinism, excessive bleeding and often lethal pulmonary fibrosis.
The molecular basis by which molecules are selectively sorted and directed to different cellular compartments in the megakaryocytes, the precursor cell for platelets, are not clearly established. The project will focus on the study of a group of proteins that play a role of "molecular switch", the Rab proteins. After activation, these proteins are able to bind a wide variety of effectors playing a role in membrane fusion or fission, or transport along the cytoskeleton. Especially Rab32 and Rab38 proteins play a key and partially redundant role in the maturation of melanosomes through binding to molecular adapter proteins AP-3. These proteins also play a role in the biogenesis of dense granules but the data are less clear and only based on the observation of tumor cell lines in vitro.
The project will determine 1) the relative location of Rab32 and Rab38 protein in organelles from bone marrow megakaryocytes; 2) their roles during different stages of platelet granule biogenesis and / or fusion of the granules; 3) the effectors of these partner proteins; 4) the possible impact of the absence of one or both proteins on the platelet function. The work will be based on the study of mouse models of HPS diseases (knockout mice the protein Rab32, Rab38 and the double knockout) by approaches in vivo, in situ, ex vivo and in vitro.
This work aims at understanding one essential mechanism of platelet functionality, with in the long term the possibility to target the secretion function of platelets as antithrombotic therapy, or to use granules as a mean to deliver therapeutic drugs. From a clinical point of view, this work will test the possibility that many patients with platelet disease of unknown etiology may have mutations in molecules involved in the biogenesis or fusion of granules. In a general point of view, this work will aim at a better understanding of cell biology regarding organelle transport and distribution in eukaryotic cells.

Wished skills: A sound theoretical knowledge in the field of cell biology. Good skills of standard biochemistry techniques and of sterile cell culture. Precision, thoroughness and motivation. Being able to work with the mouse.

Expertises which will be acquired during the training: Expertise in the biology of stem cells and platelets, stem cell isolation and culture for their differentiation, immunostaining techniques on cells or tissues, techniques of imaging microscopy (confocal microscopy, electron microscopy), biochemistry. Viral transduction.