UMR-S 1193 Inserm/University Paris Sud
Physiopathogenesis and treatment of liver diseases
Director Pr. Didier Samuel
The research Unit studies key medical and physiopathological issues on acute and chronic liver diseases including inflammatory, metabolic and cancerous diseases to understand the involved underlying mechanisms, to model some liver diseases, to accelerate translational researches and finally to discover potential diagnostic/prognostic biomarkers and therapeutic products. The molecular and cellular signaling networks which are profoundly deregulated in viral hepatitis infection, dysmetabolic and cancer diseases are investigated by several global interdisciplinary approaches and integrative biology. Implementation of such interdisciplinary projects is favored by the gathering of competences ranging from biophysics to medicine. Mechanisms of the cellular responses to stress including viral infection are investigated along different lines: cell polarity and morphogenesis, microtubule dynamics, organelle alterations, cellular trafficking, cell signaling and extracellular remodeling. The crosstalk between the gut microbiota and the liver is a major topic of the research Unit which investigates the gut/liver functional interactions, the role of innate immunity in liver cell homeostasis and finally the contribution of commensal microbiota in the initiation/amplification of inflammatory/oxidative signals. Finally, stem cell biology and cell reprogramming are applied to modeling of liver diseases and should pave the way to bioengineered organ.
The full integration of the research Unit within the Centre Hépatobiliaire is a unique opportunity to conduct translational researches from the different fundamental and clinical advances, thus leading to emergence of innovative therapeutics.
The research Unit is organized into four complementary teams.
As a continuum of the integration of the research unit within the Centre Hépatobilaire, the global objective of the translational research conducted by Team 1 is to reinforce the structuration, coordination and merging of the different fundamental and clinical components of the Centre Hépatobilaire. Such effort is expected to lead to improve transfer of research results into clinical application and the implementation of top-quality clinical studiesProject 1 : Viral infections: impact on cirrhosis and liver transplantation
The development of pathologies induces changes in chemical composition of cells and tissues. The ability to detect such chemical changes could lead to define specific signatures of the pathologies and their progression. Furthermore, the characterization of the signaling or metabolic pathways deregulated in the physiopathological processes will open the development of new therapeutic approaches. The team will address liver diseases such as dysmetabolic diseases and primary liver carcinogenesis by an integrative approach combining omics and multimodal spectroscopy. Stem cell biology and cell reprogramming will allow modeling liver diseases and will pave the way to bioengineered organ. This interdisciplinary team displays a wide range of competences in hepatology, surgery, histology, spectroscopy and omics approaches, bioinformatics and data treatment, stem and liver cell biology as well as cell reprogramming favoring the emergence of innovative therapeutics.
The research is developed along two lines: 1) study of gut microbiota remodeled by HIP/PAP lectin and their effects on inflammatory and metabolic disorders; research on proinflammatory signals circulating along the liver-gut axis and their impact on hepatocarcinogenesis. 2) Simultaneously, research on the genetic alterations involved in hepatocarcinogenesis will be extended to include the effects of inflammatory stress on the LINE-1 endogenous retrotransposition that has recently been discovered in collaboration with Dr. G. Faulkner et al. from the Mater Medical Research Institute, Brisbane. Overall, the project is expected to increase our knowledge regarding the pathogenic role of inflammation in human liver carcinogenesis and the molecular driving force of oncogenic transformation in liver cells.
In response to a huge variety of stresses of mechanic, metabolic, chemical, physical or infectious origin, cells may die or survive. Cells primarily try to cope with stressful stimuli by triggering responses that modulate gene expression and/or allow the stimulation of protective mechanisms such as autophagy induction. In the case their defenses are overwhelmed or in response to special stimuli, cells die by apoptosis and/or by necrosis. Alternatively, excessive cell adaptation and tolerance to death signals might allow damages such as genomic instability, thereby participating in carcinogenesis. In addition, a high level of adaptation may play an indirect role in sustaining inflammation and thwarting anti-tumoral immunity, thus contributing to cancer cell proliferation and tumoral invasion. Appropriate spatiotemporal coordination of cellular signaling is required to allow an optimal adaptive response to stress to take place. Such coordination involves the microtubule (MT) cytoskeleton as an organizer of the cytoplasm and of the actors of cell adaptation, as well as a target for some adaptive signals. It is indeed required to allow the correct positioning of key organelles like mitochondria or lysosomes, to support their morphological and functional changes, to organize several signalling pathways that relay stress information and are essential to the adaptive response, to allow the formation and the dynamics of autophagosomes that promote cell survival. Autophagy is one core adaptive mechanism as it allows the recycling of cellular constituents, maintains sufficient energy level, or serves as key sensor and supplier to support cell’s morphological changes.
(J. Hamelin, A. Lemoine, N. Mejdoubi-Charef, JF Morere, A. Baillet, B. Baudin, C. Poüs)