Team 1 – Genomics and Pathophysiology of Myocardial Diseases

Team headed by Philippe Charron

Team 1 focuses its research program on 4 research axes :

  • To identify key-players (rare and frequent genetic variants, signaling pathways) in cardiomyopathies and channelopathies through genomics and omics approaches.
  • To understand function, interactions and pathophysiology of key-players in these diseases through human cardiomyocytes (derived from iPS patients) and murine models.
  • To translate the new knowledge into clinical practice, especially through genetic testing and high throughput resequencing, to develop personalized medicine.
  • To progress towards new therapeutics (pharmacologic, interventional, gene-based) in monogenic or complex forms of heart failure and arrhythmias.

This team is linked to the doctoral school 394 “Physiologie, Physiopathologie et Thérapeutique”.

Principal investigators’ groups:

    • In Team 1, Pascale Guicheney and Nathalie Neyroud focus their research on genetics of hereditary cardiac arrhythmias (Brugada syndrome, long QT syndrome, short QT syndrome, and ventricular fibrillation) and functional consequences of new mutations in ion-channel subunits and associated proteins with the aim of increasing our understanding of regulatory processes of ion channels involved in human cardiac pathophysiology. They use next-generation DNA sequencing (NGS), molecular, immunohistochemical and electrophysiological techniques, associated to viral gene transfer and animal models to identify new genetic variants and to determine how variants linked to arrhythmia can alter the expression and function of cardiac voltage-gated channels.

 

  • One of team 1 research axes, led by Sophie Garnier in close collaboration with Pr. Vincent Degos of Pitié-Salpêtrière neuro-intensive care unit, aims at unravelling the predictive factors of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). Vasospam, thickening and prolonged contraction of intracranial arteries, is a severe complication of aSAH occurring 4 to 12 days after the bleeding for 15 to 20% of aSAH cases and leading to delayed cerebral ischemia (DCI) responsible for severe neurological deficiencies. To date, there is no predictive factor of vasospasm onset thus every aSAH patient is submitted to a heavy treatment not free of side effects. The discovery of cerebral vasospam predictive factors would thus improve patients nursing at their arrival in neuro-intensive care units. The used approaches to unravel these predictive factors combine transcriptomic, miRNOmic and genetic approaches.

Team 2 – Atherothrombosis and Applied Pharmacology

Team headed by J.P. Collet

The main goal of team 2 is to improve knowledge in cardiovascular medicine, from treatment strategies to education for primary prevention mainly in the field of atherothrombosis. Expanding of the group led to new areas of investigation including now cardiovascular epidemiology, education but also new technologies. Our cardiovascular research is broad going from in vitro experimental models to randomized clinical trials.

This team is attached to the doctoral school 394 “Physiologie, Physiopathologie et Thérapeutique”.

 

Team 3 – Molecular and Cellular Plasticity in Cardiovascular Diseases

Team 3 is headed by Elise Balse and Sophie Nadaud

Cardiovascular diseases are often intricate diseases that share pathophysiological mechanisms. Remodeling processes are associated with complex rearrangement at the tissue and at the cellular levels. Team 3 aims at identifying the drivers of the molecular and cellular plasticity that characterize cardiovascular remodeling during heart rhythm abnormality (atrial fibrillation), heart failure, senescence and pulmonary hypertension (PH).

We study the role of cardiovascular cells (cardiomyocytes, stem cells, inflammatory cells, endothelial cells), of molecular players (ion channels, cytoarchitectural proteins, sarcolemma), of cellular homeostasis (oxidative stress, energy metabolism). We have tight links with the functional exploration platform Coeur-Muscle-Vaisseaux led by Nathalie Mougenot for cardiovascular phenotyping.

This team is attached to the doctoral school 394 “Physiologie, Physiopathologie et Thérapeutique”.

 

Principal investigators’ groups:

Elise Balse’s group has contributed to understanding the dynamics of surface expression of cardiac ion channels and the molecular determinants of their targeting in specialized domains of cardiac myocytes. The group will continue investigating these processes in relation with the microarchitecture of cardiac myocytes in normal and diseased myocardium. The work combines cardiomyocyte isolation and culture, molecular biology, viral vectors, electrophysiology techniques (patch-clamp, microelectrode), biochemistry, immuno-histo/cytochemistry, and cellular and molecular imaging approaches (3D-deconvolution, TIRF, light sheet).

Sophie Besse and Bruno Riou’s group has identified different mechanisms contributing to the altered cardiac response to β-adrenergic stimulation during senescence and/or diabetes. This group is now investigating the regulatory pathways induced by age-associated oxidative stress and inflammation, and implicated in the transition to heart failure. The project includes hemodynamic studies, contractility measurements in isolated perfused heart and atrial trabeculae, and biochemistry and immuno-histo/cytochemistry techniques, in aged rat and human models.

Stephane Hatem’s group has uncovered the contribution of epicardial stem cells to atrial fibroadipogenic remodeling leading to atrial fibrillation. The group aims now at identifying the signaling switches that regulate the differentiation of human epicardial stem cells and the remodeling of the atrial subepicardium. The group has also started to analyze the role of cardiac metabolism in regulating atrial fibroadipogenic remodeling and electrical properties. In addition to biochemistry, immuno-histo/cytochemistry techniques, the group is using metabolomics and lipidomic approaches, human and murine epicardic progenitor cells culture, flow cytometry and electrophysiology.

Sophie Nadaud’s group has described new vascular progenitors which contribute to the remodeling of pulmonary vessels during pulmonary hypertension. The group is now studying the regulatory signals that lead to the recruitment of these progenitors and the formation of new vascular smooth muscle cells. The work combines transgenic mouse models, lineage tracing mouse models, hemodynamix studies, flow cytometry, murine vascular progenitor cell culture, molecular biology and biochemistry, immunofluorescence and histology techniques.

Catherine Pavoine’s group has established that a macrophage population plays a protective role against heart failure development during early adaptive cardiac hypertrophy. The group is now seeking to identify the origin and role of macrophages recruited and to determine the signals secreted by these macrophages during early adaptive cardiac hypertrophy which could limit adverse remodeling to heart failure. The project involves mouse models, cardiomyocyte calcium imaging, flow cytometry, RNAseq and biochemistry, immuno-histo/cytofluorescence techniques. Echocardiographic parameters of the animals are analyzed with the Coeur-Muscle-Vaisseaux platform (Dir. Nathalie Mougenot).

Florent Soubrier’s group has identified the gene, EIF2AK4, for hereditary Pulmonary Veno-Occlusive Disease and is now investigating the cellular and molecular mechanisms underlying the occurrence of the heritable form of Pulmonary Veno-Occlusive Disease due to mutation of this gene. The project involves an EIF2AK4 KO rat model, hemodynamic studies, flow cytometry, endothelial cell isolation and culture, and omics. This group seeks to identify new predisposing genes to PH by genome wide sequencing, such as the BMP10 gene recently identified by this group.

aa

Team 4 – Cellular and Systemic Lipid Metabolism in Cardiometabolic Diseases

Team headed by Wilfried Le Goff

Team 4 focuses its research on cellular and systemic lipid and lipoprotein metabolism which opens up new insights based its recent pioneer works on the identification by Omic approaches of lipid networks controlling biological activities of atheroprotective HDL and cell activation in cardiometabolic diseases. In the last few years, this team has developed translational approaches and new analytic tools for proposing new candidate genes and biomarkers with a high potential of patentability in the context of cardiometabolic diseases.

This team is attached to the doctoral school 394 “Physiologie, Physiopathologie et Thérapeutique”.

 

Team 5 – Mononuclear Phagocytes in Cardiometabolic Diseases

Team headed by Philippe Lesnik

Team 5 focuses is focused on the study of mononuclear phagocytes in the context of cardiometabolic diseases. The team main objective is to better understand how different mononuclear phagocytes subsets impact on chronic metabolic disorders, with particular emphasis on macrophages and dendritic cells. To this aim, unique mouse models and preclinical approaches are used to decipher the complex interactions between mononuclear phagocytes subsets and metabolic tissues. In addition, this team builds on recent cutting-edge preclinical and clinical proof-of-concepts evidencing a relationship between intestinal microbiota, immune cells and cholesterol metabolism in the host.

This team is attached to the “école doctorale” 394 “Physiologie et Physiopathologie”.

Principal investigators’ groups:

In team 5, Emmanuel Gautier‘s group works on the diversity and functionality of mononuclear cell subsets in cardiometabolic diseases. His group is interested in delineating the role of mononuclear phagocytes (monocytes, macrophages and dendritic cells) in chronic inflammatory conditions such as cardiometabolic diseases (atherosclerosis, obesity, NASH). More specifically, we study how dendritic cell subsets, tissue resident and monocyte-derived macrophages impact on cardiometabolic diseases development, and developed tools to target these subsets in vivo. Our studies are based on integrated approaches combining molecular, cellular biology and animal models. Particular attention is given to the interactions between inflammatory stimuli, mononuclear phagocytes, lipid and carbohydrate metabolisms as well as the gut microbiota.

aaa