Team 2

Thrombosis platelets and vascular diseases

Supervisors

Pierre MORANGE

Franck PEIRETTI

Team members

Alessi Marie-Christine (PUPH, AP-HM, Amu)
Badens Catherine (PUPH, AP-HM, Amu)
Bonnet Jean-Louis (PUPH, AP-HM, Amu)
Cerino Mathieu (MCUPH, AP-HM, Amu)
Chambost Hervé (PUPH, AP-HM, Amu)
Cuisset Thomas (PUPH, AP-HM, Amu)
Desgrouas Camille (MCF, Amu)
Dutour Anne (PUPH, AP-HM, Amu)
Gaborit Bénédicte (PUPH, AP-HM, Amu)
Hezard Nathalie (PH, AP-HM)
Ibrahim-Kosta Manal (MCUPH, AP-HM, Amu)
Poggi Marjorie (MCF, Amu)
Sarlon Gabrielle (PUPH, AP-HM, Amu)
Saultier Paul (MCUPH, AP-HM, Amu)
Suchon Pierre (MCU-PH, AP-HM, Amu)
Thomas Grace (CR, Inserm)

New pathophysiologic pathways involved in thrombosis; from bedside to the bench

Pierre Morange

This topic aims to identify new pathophysiologic pathways involved in hemostasis and venous thrombosis (VT). We are using omic strategies in large patient cohorts. These cohorts are implemented with biobanks allowing the analysis of plasmatic and genetic markers. A pangenomic study allowed us to identify new genes associated with VT, genes that do not belong to the classical coagulation/fibrinolytic cascades, thus opening new paths to the discovery of new pathophysiologic pathways. Other omic approaches are ongoing in national and international networks.

Concerning the fundamental level, we are characterizing the newly discovered pathways and we are focusing our research on the role of unexplored transmembrane proteolysis in the regulation of hemostasis and thrombosis.

We are studying the CTL2 protein (choline transporter like protein-2) and its interaction with von Willebrand factor (VWF) in dynamic conditions but also using animal model of inflammation and thrombosis. This project is supported by a young researcher ANR grant. In parallel we have identified a protective role of the inflammatory molecule LIGHT (TNFSF14) during atherosclerosis and in the associated thrombotic complications. We are currently trying to decipher the molecular mechanisms involved by studying the role of LIGHT on the thrombogenicity of the atherosclerotic plaque and platelet reactivity.

We are interested in the proteases responsible for the cleavage of cell surface proteins. We are looking at different aspects of their regulation (synthesis, cellular trafficking, maturation, activation, membrane organization…) and also at the impact of their regulation on the cleavage of their substrate. We are also looking at the biologic and pathophysiologic consequences of these regulations. Thrombomodulin (TM) is a transmembrane protein, expressed at the vascular endothelial cell surface, that has antithrombotic properties. TM has been identified as a substrate of the intramembrane serine protease Rhomboid-like 2 (RHBDL2). We are studying the regulation of TM cleavage by RHBDL2 in the vascular endothelium and the consequences of this cleavage.

This work represents a unique opportunity to understand new mechanisms involved in thrombotic disorders in order to improve the diagnosis tools and therapies for patients suffering from TV.

KEYWORDS: THROMBOSIS, HEMOSTASIS, PHYSIOPATHOLOGY, PROTEOLYSIS, CTL2, thrombomodulin, TNFSF14/LIGHT

Platelets and vascular pathologies

Marie-Christine Alessi

Following damage to a blood vessel, platelets bind to the wall of the damaged vessel to prevent excessive blood loss. In pathological situations, they cause thrombosis, which can lead to a myocardial infarction or stroke. Since 2009, our team has been interested in the molecular mechanisms of platelet pathologies of genetic origin and aims to better understand these pathologies by identifying new genes at the origin of these pathologies, by improving our knowledge of platelet activation, by developing new exploration tools and by studying the role of proteolysis in platelet function. For the first time, we have identified RASGRP2 variants as an important cause of platelet dysfunction leading to severe bleeding, and the platelets of patients with RASGRP2 variants represent unique tools for the study of regulatory pathways for platelet activation. The study of these platelets has allowed us to identify an aggregation-inhibitory signaling pathway that is dependent on Protein Kinase C. We are working to characterize this pathway in order to identify new strategies for modulating platelet reactivity. In parallel, we have characterized the effects on platelet production of variants of the ETV6 and FLI1 genes encoding two transcription factors expressed by platelet precursor cells. Our work aims to further investigate the effects of these mutations by applying methods to study protein/DNA interaction and gene expression. BACE1 is the enzyme that cleaves the amyloid precursor peptide. BACE1 and some of its substrates are expressed in blood platelets. Platelet expression of BACE1 has been proposed as a marker for Alzheimer's disease but the role of BACE1 in platelet reactivity, and more broadly in platelet biology, has never been explored. The group proposes to evaluate the role of platelet BACE1 by studying the impact of its inhibition and/or absence on platelet aggregation and platelet half-life.

Main publications

Keywords: platelets, thrombopathies, thrombopenia, proteolysis, signaling

Ectopic fat and vascular risks

Anne Dutour & Bénédicte Gaborit

This research theme focuses on links between obesity, type 2 diabetes and cardiovascular risk through the study of ectopic fat deposits. These public health problems has reached pandemic
proportions, it is a priority to identify patients who will develop vascular complications, making the prognosis of these diseases all the more serious.

Our objectives are to develop non-invasive and relevant imaging tools to quantify ectopic fat in
severely obese patients. Indeed, the clinical examination is not very informative, and conventional paraclinical evaluations are often taken in default. We have already developed new methods to
quantify ectopic fat in obese subjects on MRI (epicardial fat volume, intra-organ triglyceride content, cardiac energy metabolism) and we are studying how to improve these methods using new technologies (high field MRI) in collaboration with CEMEREM and Dr. Bernard's CRMBM. We are also studying the morpho-functional, secretory characteristics of cardiac ectopic fat in order to identify new molecular bases of preferential fat accumulation at the cardiac and peri-coronary levels. Our hypothesis is to propose a paracrine effect of epicardial adipose tissue on adjacent tissues and we use in vivo models to better characterize the phenotype of this fat. Finally, we are involved in a European project aiming at identifying the specificity of diabetic cardiomyopathy through a multiomic
approach.

Another line of research focuses on the cardiovascular and microangiopathic safety of anti-diabetic treatments, with a particular focus on the impact of GLP-1 receptor agonists and sodium glucose transporter 2 inhibitors on ectopic fat deposits and vascular complications (heart disease, diabetic retinopathy, angiogenesis). We are working to identify circulating miRNAs and immune cells that characterize patients who will develop retinal and vascular complications, and we are developing translational approaches for personalized and precision medicine. Our goal is to develop new biomarkers of diabetic retinopathy in order to prevent this serious complication often responsible for blindness.

Main publications

KEYWORDS : EPICARDIAL ADIPOSE TISSUE, TYPE 2 DIABETES, OBESITY, CARDIOMYOPATHY, RETINOPATHY,
ECTOPIC FAT DEPOT, MAGNETIC RESONANCE IMAGING

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Publications theme 1

Publications theme 2

Publications theme 3

Team 2

Thrombosis platelets and vascular diseases

Team members

New pathophysiologic pathways involved in thrombosis; from bedside to the bench

KEYWORDS: THROMBOSIS, HEMOSTASIS, PHYSIOPATHOLOGY, PROTEOLYSIS, CTL2, thrombomodulin, TNFSF14/LIGHT

Platelets and vascular pathologies

Main publications

Keywords: platelets, thrombopathies, thrombopenia, proteolysis, signaling

Ectopic fat and vascular risks

Main publications

KEYWORDS : EPICARDIAL ADIPOSE TISSUE, TYPE 2 DIABETES, OBESITY, CARDIOMYOPATHY, RETINOPATHY,
ECTOPIC FAT DEPOT, MAGNETIC RESONANCE IMAGING

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