Congenital heart diseases (CHD) are the most frequent congenital diseases. GWAS and exome sequencing performed for the last decade revealed mutations in coding sequence in only a minority of CHD patients. Rather a high proportion of hits in epigenetic modifiers was found. Furthermore environmental factors including nutrition of mothers impacting epigenetic regulation of gene transcription are likely to play a role in CHD. Thus, the team physiopathology of cardiac development focuses its research on epigenetic regulation of cell fate determination during cardiac embryonic development. We are aiming at finding therapeutic targets for rare diseases including an epigenetic component such as laminopathies, Cornelia de lange syndrome (nipbl mutations) , metabolic diseases. We also focus our reaserch on Tetralogy of Fallot and valve development and diseases, as they represent altogether 50% of cardiac congenital defects. These pathologies either lead to heart failure at the adulthood or become prominent in the aging population, respectively. Our research is also dedicated to better design strategies of cell therapy and its cell mechanisms to regenerate the right ventricle for repaired tetralogy of Fallot, a complex cardiac congenital disease, for which reparation of the septal defect at birth has consequences on adult right ventricular function. To more specifically address such a broad biological question, we carry out different projects using patient specific iPS cell lines, cardiac organoids and mouse models of diseases ( lmnaH222P/H222P; Nipbl+/-, lineage specfic deletion of nipbl; ApoE-/-a model of valve calcification...)
- The Cornelia de Lange syndrome: in collaboration with Valérie Cormier-Daire (Imagine Institute , Paris) and Erwan Watrin (Erwan WATRIN | Institut Génétique & Développement de Rennes (univ-rennes1.fr). We are specifically focused on a druggable cell pathway over-activated in CdL syndrome in order to alleviate consequences of the syndrome on cardiac defects.
- Cell fate determination during cardiac valvulogenesis and identification of drugable targets of cell pathways responsible for calcific aortic diseases: we are using a clonal analysis combined with a single cell-sequencing approaches; We are targeting specific pathways of valve formation and calcification to design pharmacological therpeutic approaches. In collaboration with Jonathan butcher Jonathan T. Butcher | Cornell Research
- The laminopathy at the origin of a cardiomyopathy: a congenital disease with an epigenetic origin: in collaboration with Gisèle Bonne Institute of Myology (Institut de myologie, Paris). We are specifically focusing our resarch on the embryonic origins of the disease both for the dilated cardiomyopthy and conduction defects.
- The role of epigenetics in vitamin D deficiency and CHD: We specifically focus on the impact of vitamin D combined or not with high fat diet on heart formation and the consequences in adult myocardial and valve diseases in collaboration with Jean-Francois Landrier (Micronutrition humaine - C2VN Centre de Recherche en CardioVasculaire et Nutrition (univ-amu.fr))
- The role of embryonic senescence in heart formation: We have identified senescent cardiomyocytes in embryonic hearts expressing specfic markers revealed by single cell-seq. We aim at understanding the role of these cells in patterning cardiac territories and the role of metabolism and epigenetics in this cell process. we further investigate how rare metabolic syndromes use these pathways to impact heart formation. We are using genetic lineage tracing, single cell-seq and spatial transcriptomics in mice as well as in vitro in cardiac organoids to screen senolytic and pro-senescence drugs also used in oncology (in collaboration with marisa Jaconi (http://www.unige.ch/medecine/pati/en/groupes/536jaconi/) and Vladimir Katanaev (hiGE3 website - Katanaev Group (unige.ch)
- Cardiac Regeneration in a pig model of cardiac congenital disease : in collaboration with Virginie Lambert (Equipe - Cardiologie - IMM | Institut Mutualiste Montsouris) with the pediatric cardiology service La timone Hospital ( Service médico-chirurgical de cardiologie pédiatrique et congénitale - Hôpital de la Timone) , CERIMED (CERIMED) and the IHU the Lyric (Les projets de recherche | IHU Liryc - L'institut de rythmologie et modélisation cardiaque - Bordeaux (ihu-liryc.fr). We are investigating the role of specific cell processes in the recovery of function triggered by cell therapy of the failing right ventricle.
The head of the team Michel Puceat is an INSERM director of research. He has signed more than 135 publications (HI 45). He has acquired a background of cardiac biochemistry and physiology as well as cardiac developmental biology.
