Left ventricle hypertrophy (LVH) is an adaptive response of the heart to an increase workload. At the beginning, LVH is beneficial to maintain cardiac output by reducing wall stress, but it becomes maladaptive in the chronic phase, resulting in heart failure (HF). HF remains a deadly syndrome with 5-year mortality of 40-60%. Advancement of the understanding of the mechanisms underlying LV remodeling and the transition to HF is a prerequisite for the development of new efficient management strategies. A prominent and unique feature of cardiac muscle is the presence of intercalated discs (ID) at polarized ends of cardiomyocytes. ID are the “glue” which ensures mechanical and electrical coupling from one cardiomyocyte to another. Soon after birth, the cardiomyocytes elongate, ID are organizing toward a mature state. Human studies have shown that during LVH process, hypertrophied myocytes harbor dedifferentiated phenotype (ID destructuration, sarcomere depletion, glycogen accumulation, and alteration of mitochondria). It is proposed that these changes toward a fetal-like phenotype represent an adaptive programmed cell survival response. However, the biology of this phenomenon of recapitulation of an immature phenotype of the failing myocardium is largely unknown. The global objective of this proposal is to decipher new molecular mechanisms driving the LV remodeling and the transition to failure. Wnt/Planar Cell Polarity (PCP) pathway has recently emerged as a major regulator in adult organs for tissue morphogenesis. This ubiquitous system coordinates cellular communications; it involves polarized coupling between adjacent cells. By applying PCP features to heart morphogenesis, we hypothesize that the Wnt/PCP pathway may signal in the cardiomyocytes and control their polar organization and their remodeling and in fine the molecular balance from dedifferentiated immature toward a differentiated a phenotype and vice versa. Our working proposed model is that Wnt/PCP signaling is required during fetal maturation, for the organization of cardiomyocytes (immature phenotype) and is repressed when cardiomyocytes undergo differentiation In this project, we have asked whether Wnt/PCP signaling is reactivated during hypertrophic cardiomyopathy development and involved in HF. Our objective is to decrypt PCP signaling and its role in the process of cardiac morphogenesis. It will be the first demonstration that PCP signaling is involved in the physiopathology of the transition from LVH to HF. The core molecular machinery and regulation of PCP pathway is far to be known in mammals. We have recently identified a novel actor of PCP pathway: the ubiquitine E3 ligase, PDZRN3 and demonstrated its upstream critical role in the regulation of the Wnt/PCP signaling. To tackle this project, we have then developed original tools to overexpress and to delete specifically Pdzrn3 in cardiomyocytes in vivo (transgenic mice) and in vitro. In order to better understand the physiopathology basis of this reported phenotype of Pdzrn3 mutant mice, we have collected cardiac human tissues from patients suffering from various cardiomyopathies. Utilization of animal and cellular models to probe causes and mechanisms of cardiomyopathy disease will result in breakthroughs in diagnosis or prognosis tools or in development of novel treatments that will hopefully improve the outcome for HF patients.

Elements such as Ca and Mg are crucial in many synthetic and natural materials, including bones and teeth. The intrinsic structural complexity of these materials calls for the development of original and advanced characterization techniques. New and promising preliminary results obtained by 43Ca DNP (Dynamic Nuclear Polarization)-enhanced NMR (Nuclear Magnetic Resonance) at natural abundance (0.14 %) have shown that an unprecedented description of chemical environments around Ca atoms can be reached (distinction of surface and core sites in nanomaterials), circumventing the ultra-low sensitivity of 43Ca! Thus, the objectives of the project are: (i) methodological development of the DNP-NMR experiment, (ii) optimisation of this new technique for the description of Ca and Mg environments in synthetic biomaterials, (iii) in-depth study by 43Ca and 25Mg DNP-NMR of bones of normal and genetically engineered mice, in view of expanding our understanding of human bone pathologies.