The Team
  • Researchers

    Agnès BLOCH-ZUPAN

    Pascal DOLLE

    Virginie HAUSHALTER

    Wojciech KREZEL

    Karen NIEDERREITHER

  • Post-Doctoral Fellows

    Vito Antonio BALDASSARRO

    Marion CIANCIA

  • PhD Students

    Lucile CATHIARD

    Alexandra JIMENEZ ARMIJO

    Joanna SOBSKA

  • Engineers & Technicians

    Valérie FRAULOB

    Brigitte SCHUHBAUR

  • Collaborateur Occasionnel

    David WARTHER

Development and stem cells

Brain development and physiology

Whereas vitamin A is best known for its critical role during embryonic development and visual cycle (documented by 3 Nobel prizes), its post-natal activities, including in neuroprotection, modulation of neurotransmission and synaptic plasticity only start being discovered and understood. Our goal is to decipher the highly diverse functions of vitamin A, its active derivatives (retinoic acids), and the corresponding nuclear receptors (RARs/RXRs), in neural development, aging, and in stem cell control. An immediate objective  is to determine how specific retinoid receptors, synthesizing enzymes and bioactive metabolites control development and function of specific cell types and relevant neural circuits. We investigate how such modulations affect adult brain physiology and function. To address these questions we use mouse models with targeted gene inactivations, as well as CRISPR- and viral-based approaches to control gene expression, in combination with genomic, proteomic and metabolomic analyses. In collaboration with experts in chemistry we also develop new tools to study biological processes in vivo (e.g. click chemistry, novel RXR agonists). We have shown that fine-tuning of retinoic acid activity depends on its spatiotemporal patterns of synthesis (by retinol and retinaldehyde dehydrogenases) and catabolism (by CYP26 enzymes). Our current focus relates to the role of retinoids in brain physiology and pathology, with a particular interest in basal ganglia and dopaminergic signalling, whose dysfunctions are associated with several neuropsychiatric disorders. These studies take advantage of murine models relevant to neurodevelopmental disorders, Parkinson’s and Huntington’s disease, and depression. A long-term goal is to understand the mechanisms underlying these disorders, and develop new strategies or compounds for their prevention or therapy. We have recently deposited several patents and are collaborating with clinicians to accomplish this objective.

  • Current projects

    Role of retinoids in development and pathophysiology of the dopaminergic system

     

    Even subtle alterations in dopaminergic signalling may affect brain functions, and may underlie various neuropsychiatric diseases. Our ongoing projects related to dopaminergic system are focused on basal ganglia including striatum, a brain region important for control of motor, affective and cognitive functions. The goal is to understand how discrete developmental events contribute to physiological diversity in cognitive performance, or affective susceptibility to stress, and understand the neurodevelopmental basis of neurologic diseases (e.g. restless legs syndrome, and selected rare diseases). We are testing known and newly characterised retinoids for treatment of such brain disorders in relevant animal models.

     

    Retinoids in prevention and treatment of depression

     

    Stress-related disorders such as depression result from increased genetic susceptibility to environmental stressors. Nuclear receptors, including RARs and RXRs, are well suited to form a dynamic interface between environment and genome as they act as ligand-regulated transcription factors and can sense nutrients, hormones and xenobiotics, translating such signals into transcriptional, adaptive responses. Our recent data on mechanisms of depression induced by Accutane® (13-cis-retinoic acid), the only curative treatment of acne vulgaris, reveal existence of genetic susceptibility factors to develop depression under this treatment. We aim to propose novel diagnostic and prevention methods in order to prevent the risk of Accutane-induced depression, as well as tools to prevent or treat depression as a common disease.

     

    Retinoids in prevention and treatment of neurodegeneration

     

    Recent data point to neuroprotective effects of specific retinoic acid-synthesizing enzymes or retinoid receptors in distinct brain regions. Do such effects reflect local production of bioactive retinoids, and/or specific functions of distinct RAR isotypes? Answering those questions should lead to new targets to fight neurodegeneration, whereas studies of neuroinflammation and mitochondrial functions, as potential mechanisms of retinoid actions, should allow to better understand the process of neuroprotection. We evaluate neuroprotective potential of synthetic and recently characterized endogenous retinoids in relevant animal or cellular models.

     

    New tools for studies of biological processes and drug development

     

    A recurrent challenge in modern biology is to integrate into a more global picture molecular, cellular and functional determinants of a given biological process. In collaboration with experts in synthetic, analytical and biological chemistry, we elaborate tools for multilevel studies of small bioactive molecules or circulating drugs in living organisms. The key to such approaches are rapid and irreversible chemical reactions ("click chemistry"), which can be carried out in a complex biological environment.  A prototypic example is the development of click chemistry reactions in the living organism, which we showed useful for rapid inactivation and renal elimination of a purpose-designed drug. This work paves the way for new strategies in drug design and studying of endogenous metabolic or signalling processes.

  • Collaborations

    Angel deLera (chemical synthesis and modeling), University of Vigo, Spain

    Emmanuel Haffen (clinical and experimental psychiatry), Centre Hospitalo-Universitaire Besançon, France

    Shin-Ichi Muramatsu (viral vector approaches for gene therapy), Jichi Medical School, Japan

    Ralph Rühl (analytical chemistry), University of Debrecen, Hungary

    Miguel Torres (developmental biology), CNIC Madrid, Spain

    Alain Wagner (biological chemistry), University of Strasbourg, France

    Juliane Winkelmann (neurology, neurodevelopmental diseases), Helmholtz Zentrum München, Germany

  • Prizes/Awards

    • Agnès BLOCH-ZUPAN - Micheline-Blain prize - Réseau de recherche en santé buccodentaire et osseuse - 2016
    • Agnès BLOCH-ZUPAN - Sciences Award - Académie Rhénane - 2015
    • Agnès Bloch-Zupan - USIAS Fellowship 2015 - USIAS (Institut d'études Avancées de l'Université de Strasbourg) - 2015
    • Pascal DOLLE - Chevalier of the National Order of Merit - Etat français - 2013
    • Agnès BLOCH-ZUPAN - Prize of Hospital Odontology - Conférence des Chefs de Service d'Odontologie en partenariat avec MICRO-MEGA - 2005
    • Wojciech KREZEL - Young Investigators Award - Inserm - 2004
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Imprimer Envoyer

Université de Strasbourg
INSERM
CNRS

IGBMC - CNRS UMR 7104 - Inserm U 1258
1 rue Laurent Fries / BP 10142 / 67404 Illkirch CEDEX / France Tél +33 (0)3 88 65 32 00 / Fax +33 (0)3 88 65 32 01 / directeur.igbmc@igbmc.fr