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UMR 1141 "NeuroDiderot" Inserm - Université de Paris

NeuroDiderot is a research Unit created in January 2019. It comprises 5 teams resulting from the fusion of UMR 1141 (Neuroprotection of the developing brain; 3 teams; P Gressens; Robert Debre Hospital), UMR 1161 (Genetics and pathophysiology of neurovascular disorders; 1 team; E Tournier-Lasserve, Diderot Medical school, Villemin campus) and UMR 1129 (Childhood epilepsies and cerebral plasticity; 1 team; C Chiron; Necker Hospital and NeuroSpin and the SHFJ of the CEA).

These 3 UMRs have a deep and long-standing relationship (UMR 1141 has collaborated for many years with UMR 1161 and UMR 1129, and UMR 1161 and UMR 1129 have close, well-established links with each other and different teams of NeuroSpin), and have been focused for more than 2 decades on neurodevelopmental and neurovascular disorders.

The new Unit is mainly located at Robert Debre Hospital, with high-field MRI and PET scan facilities being located at CEA. The research laboratories are located on the 3rd and 4th floors of the Bingen building of Robert Debre Hospital (this building is situated 30 meters from the main building of the hospital, and is linked to the latter by several skywalks). These two floors (2,000 m2) are entirely dedicated to our Unit. In addition, a vivarium (500 m2) is located on the 5th floor of the Bingen building, and the 6th floor of the same building hosts a library (shared with the hospital) and an Inserm conference room.

 

 The structuring of the Unit is as follows:

Team 1 : Neurokines
Glial homeostasis, neuroinflammation and neuroprotection (P.Gressens & P.Dournaud)

Team 2 : NeuroDev
Cellular dysfunctions in neurodevelopmental disorders (O.Boespflug-Tanguy & N. de Roux)

Team 3 : NeoPhen
New tools for physiological data processing in early neurodevelopmental disorders (C. Delclaux & B. Matrot)

Team 4 : GenMedStroke
Genomic and personalized medicine in neurovascular disorder (E. Tournier-Lasserve & H. Chabriat)

Team 5 : InDev
Anatomo-functional variability, vulnerability and plasticity during neurodevelopment : clinics, behavior and imaging (L.Hertz-Pannier & J. Dubois)

 

Team 1. The overarching goal of the research program of Team 1, NeuroKines, led by Pierre Gressens (DR inserm) and Pascal Dournaud (DR Inserm), is to identify and test new targets for neuroprotection in appropriate preclinical animal models, and to apply this new knowledge to neonates and children in a translational approach, with a view to improving their care and neurocognitive outcome. We seek to do this by increasing our knowledge of the developmentally regulated vulnerability of the brain, by focusing on innovative ways to decipher the mechanisms of brain injury and by developing appropriate neuroprotective strategies. Candidate neurotherapeutics are tested across a range of animal models of clinically relevant perinatal insults, with the aim of bringing the most promising protective strategies to clinical trials.

Team 2. The team NeuroDev led by Odile Boespflug-Tanguy and Nicolas de Roux, combines experts in experimental and clinical research in the field of neurodevelopmental disorders. Brain development is associated with a series of developmental sequences including the proliferation, migration and differentiation of neurons and glial cells. In humans, it is a particularly long process starting in early embryonic life and lasting up to the end of adolescence. These sequences of events are not fully programmed but rely on developmental checkpoints. Altering these sequences through genetic mutations or environmental insults leads to phenotypic alterations and lifelong neurological and psychiatric disorders, termed Neurodevelopmental Disorders (NDDs). Later in the lifespan, neurodegenerative diseases could also result from perturbations in late developmental sequences and/or the impairment of brain maintenance. The complexity of human brain development renders human monogenic genetic disorders unique models to decipher the key mechanisms involved. Our work focuses on inherited NDDs affecting: antenatal or postnatal brain growth (microcephalies), white matter development (leukodystrophies), rare neuronal disorders characterized by a pubertal defect.

Team 3. NEOPHEN: NEW TOOLS FOR PHYSIOLOGICAL DATA PROCESSING IN EARLY NEURODEVELOPMENTAL DISORDERS
The management of sleep-related breathing disorders is a major issue in public health, especially during the neonatal period. Recently, major discoveries have been made on the neurological basis of respiratory rhythm generation in mice, paving the way for the development of new diagnostic tools and treatments. In the clinical context, the past few years have seen the emergence of tools based on advanced signal processing of physiological data.
In this context, our team conducts technological research to develop new tools for physiological data processing in early neurodevelopmental disorders, at the preclinical level in newborn mouse models of pediatric diseases, and at the clinical level in patients with ventilatory and sleep disorders.

Our objectives are:
- to develop new tools based on advanced signal processing of physiological data to characterize the control of breathing disorders
- to study genetic determinants of the control of breathing, identify its neural substrates in health and disease
- to design and test candidate treatments in sleep-related breathing disorders

Our work finds applications in research on several pediatric diseases, from rare diseases such as CCHS (Congenital Central Hypoventilation Syndrome) and Auriculo-condylar Syndrom to sleep apnea, narcolepsy, myopathy or SUDEP (Sudden unexplained death in epileptic patients). Our team is composed of experts in the fields of physiology, mathematics and physics, signal and video processing, mechanical and electronic engineering, biomedical engineering, and preclinical and clinical trials.

Team 4. GENMEDSTROKE: GENOMIC AND PERSONALIZED MEDICINE IN NEUROVASCULAR DISORDERS

Team 4 GeneMedStoke research goals are to improve the etiological diagnosis of hereditary cerebrovascular diseases (CEVD) by identifying their genetic determinants, to obtain a better understanding of their pathophysiology by combining studies in patients and mouse models, and to apply this knowledge to expand the scope of treatment using new preventive, diagnostic and therapeutic approaches.      

This translational research benefits from the strong links between Team 4 and the service de Génétique Neuro-vasculaire (the National Reference Genetics lab for Neurovascular disorders; NRGN), the service de Neurologie and the CERVCO (National Clinical Reference Center for Rare Vascular disorders affecting the brain and the eye), 3 hospital Lariboisière based structures, headed by the 2 team leaders. In addition, the team coordinates the Hospital-University Department (DHU) NeuroVasc Paris-Sorbonne.      

We are currently using a combination of various pan-genomic and candidate gene networks approaches to identify the molecular basis of fetal intracerebral hemorrhage, a devastating condition whose etiology remains elusive in more than 85 % of fetuses, precluding any genetic counseling. Using the same approaches in combination with the development of novel statistical tools, we also investigate large series of adult patients with “extreme” cerebral small vessel diseases phenotypes of unknown etiology. Following gene identification of some of these CEVD, such as cerebral cavernous malformations, we have developed mouse models that we use for preclinical trials, with the final goal of developing clinical trials for patients for whom no curative treatment is available so far. 

We are also studying the natural history of different hereditary CEVD, the variability of their clinical manifestations and their potential predictors during longitudinal studies. We particularly evaluate different types of imaging markers in rare CEVD patients to understand their variability, clinical correlates and predictive value for preparing future clinical trials. In the most frequent of these conditions, CADASIL, we develop innovative tools for investigating microstructural tissue changes or vascular dysfunction at an early stage of the disease that might be used for evaluating potential drugs at the onset of cerebral lesions. We also aim to develop new tools for better evaluating white-matter lesions that vary not only during the course of cerebral small vessel diseases but also according to their genetic origin.

Team 5. INDEV: ANATOMO-FUNCTIONAL VARIABILITY, VULNERABILITY AND PLASTICITY DURING NEURODEVELOPMENT : CLINICS, BEHAVIOR AND IMAGING      

Neurodevelopmental disorders (NDDs), characterized by an early focal or diffuse brain malfunction, lead to variably severe disorders of the cognitive functioning in children. These common (up to 10% of an age range) and pleomorphic conditions manifest as perturbations of multiple learning processes, more or less associated with sensorimotor symptoms. Appropriate management and/or treatment of both these pathologies and their co-morbidities suppose a better characterization of their underlying neurobiological substrates, their commonalities and their interactions. The dynamics of individual phenotypes during childhood relies on critical mechanisms of brain plasticity that are specific to the immature brain and depend on both physiological variability and environmental influences.

  The in DEV team focuses on the characterization of the anatomical and functional variability of brain development, in close relationship to neurological and cognitive functions, from birth to adolescence, longitudinally whenever possible, in selected pathological conditions and in close link with the typical development dynamics. We use a multimodal approach combining various biomarkers, both behavioral (neuropsychology, experimental psychology, oculometry), and imaging (advanced MRI, PET-MRI, High density EEG, functional Ultrasound). The pathological models studied do share an early determinism, either pre- or perinatal : embryo-fœtopathy caused by prenatal alcohol exposure, early malformations of cortical development (especially with temporal lobe epilepsy, in relation with early memory development), various conditions of the 3rd trimester of pregnancy (premature birth, intra-uterine growth restriction…), perinatal brain injuries (with/without cerebral palsy), and early language disorders (oral and written language) with their family predisposition.

  The team is localized on 2 sites, Robert Debré University Hospital (APHP, Paris) and NeuroSpin (Neuroimaging research center, CEA-Saclay), to optimize interactions between clinical and basic research, for the sake of studying pediatric cohorts of fragile patients at Robert Debré Hospital. Interactions are facilitated by the use of similar imaging equipment on both sites (3T MRI and EEG), while benefitting from advanced data acquisition/analysis methodologies at NeuroSpin (7T MRI, MEG, neurocomputational approaches, biomathematics, in silico models …).

  The team fosters collaborations in basic neurosciences with other NeuroDiderot teams whose research fields are close with additional focus in preclinical research, and collaborations in cognitive and developmental neuroscience with U992 (Neurospin, CEA-Saclay). We are taking benefit from our collaborations with Robert Debré hospital clinical teams (neonatal care, neuropediatrics, child psychiatry…), as well as with national and international (Netherlands, Switzerland..) pediatric research networks and methodological teams of NeuroSpin, CEA-Saclay, and in the US.

                           

 

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