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Team 1 : Integration of transcriptional responses inducted by thyroid hormones and their receptors (Demeneix)

par Administrateur - publié le , mis à jour le

Overview

Our team has the overarching objective of analysing how thyroid hormone signalling is integrated in whole body physiology during development and ageing. Through our reseach we are examining the possibility that there exists a common cellular basis, for two apparently distinct areas of thyroid function : metabolism and orchestration of developmental processes. Metamorphosis in fish and anuran amphibians are striking examples of TH-dependent developmental remodelling. Metamorphosis can be seen as a parallel to mammalian postnatal development, with marked TH changes occurring in the maturing nervous system (1), intestine (2) and bone (3). These remodelling events require tissue renewal through production of new components (4). Given the links between senescence and tissue renewal capacity and the inverse correlations of TH hormone levels with longevity (see Bowers et al., 2013) we propose the hypothesis that TH availability in renewable tissues controls metabolic responses and self-renewal and regenerative capacity.

Our on-going projects bring together results from two main aspects of our previous work, central hypothalamic control of TH availability and TH control of stem cell niches. The team is examining first, if the apparently distinct sets of effects (i.e. metabolism and morphogenic remodelling) are linked at the cellular and whole organism levels through cell-specific changes in TH availability and second, whether controlled, differential abrogation of TH availability in renewable tissues is related to regenerative capacity and longevity.

Currently we have four main research axes :

  • To determine how changes in central, hypothalamic TH availability and action during development affect metabolism, tissue renewal and longevity,
  • To discover how cellular transitions in the adult neural stem cell (NSC) niche relate to local changes in TH hormone availability, gene expression, epigenetic signatures and cellular metabolism,
  • To identify TH-induced epigenetic changes determined during development with a potential for reversibility using the regenerating heart as a model,
  • To examine how thyroid hormone signalling during development can be modulated by xenobiotics. This research axe on endocrine disruption has led to the creation of a start up WatchFrog that carries out environmental screening and chemical testing.
  • This research also led to CNRS awarding Barbara Demeneix the Medal for Innovation in 2014.

A major feature of our research is the close collaborations with many leading European laboratories through multiple EU contracts. Examples include the co-ordination of CRESCENDO (2005-11), a FP6 EU Integrated Project on Nuclear Receptors in Development and Aging and SWITCHBOX (2011-15), a FP7 EU Collaborative Project on maintaining health in old age through homeostasis.
The team of Barbara Demeneix is currently participating in the following European projects :

  • DevCom (2013-17), a FP7 Initial Training Network (ITN) to train young researchers in developmental biology, computational biology and systems biology
  • HUMAN (2013-18), a FP7 collaborative project studying the functional link between genetic risk variant and metabolic diseases
  • EDC-MixRisk (2015-19), a H2020 collaborative project which focuses on the effects of mixtures of endocrine disruptive chemicals (EDCs) on children by developing methods for risk assessment
  • THYRAGE (2016-20), a H2020 collaborative project investigating the effects of thyroid hormone on adult stem cell populations implicated in a wide range of age-related diseases
  • HBM4EU (2017-2021), a joint effort of 26 countries co-funded by Horizon 2020 which aims to coordinate and advance human biomonitoring in Europe, thereby providing better evidence of the actual exposure of citizens to chemicals and the possible health effects to support policy making.

Models and Experimental Approaches :

The central hypothesis tested is whether modulation of cellular metabolism induced by changes in TH availability affect cell division/differentiation choices and how, in turn, switching on or off TH target gene responses during development or maturity can favour regenerative capacity and longevity. As TH integrates whole body homeostasis centrally in the hypothalamus and locally by governing tissue specific responses, three physiological systems will be analysed : hypothalamic control of the thyroid axis and metabolism in different mouse strains ; NSC renewal in xenopus and mice ; and heart regeneration in zebrafish, amphibians and mice. Experimental approaches include physiological and genetic interventions to modulate TH availability during development. Consequences are assessed at the levels of the organism (longevity, metabolism), tissues (renewal or regenerative capacity, morphological approaches, genome wide transcriptome and methylome analyses combined with metabolomics studies) and cells (histology, cell-choices and population shifts).

Staff :

Team Leader

Barbara Demeneix, PR MNHN
barbara.demeneix@mnhn.fr
01.40.79.36.07
www.bdemeneix.wordpress.com

Permanent Staff

Researchers, professors and assistant professors

Laurent Coen, MC MNHN
Amaury de Luze, PR MNHN
Jean-Baptiste Fini, CR CNRS
Marie-Stéphanie Froidevaux, PR MNHN
Fabrice Girardot, MC MNHN
Sylvie Remaud-Jachiet, MC MNHN

Research Engineers, technicians

Karine Le Blay, IE CNRS
Sébastien Le Mével, IE MNHN
Louise Péricard, TCN MNHN
Isabelle Seugnet, IR CNRS

Temporary Staff

Research Engineers, technicians

Lamis Chamas, IE CNRS
Stéphanie Decherf, IR CNRS
Cristina Luongo, IR CNRS
Anthony Sebillot, IE CNRS
Petra Spirhanzlova, IR CNRS/MNHN

PhD Students

Jean-David Gothié
Michelle Leemans
Lindsey Marshall
Bilal Mughal