INP - UMR 7051

Institute of NeuroPhysiopathology

Director : Michel KHRESTCHATISKY

Faculté Médecine Nord
CS80011
51 Bd Pierre Dramard
13916 Marseille CEDEX 20
France

With complementary skills in animal models and in vitro models, the 4 research teams of the laboratory study the cellular and molecular mechanisms underlying the neural basis of brain function and malfunction. In particular, they are interested in neuronal plasticity and memory, as well as neurodegenerative and neuroinflammatory processes involved for example in Alzheimer’s disease, multiple sclerosis or spinal cord injuries. This research is directly applied in i) cell therapy approaches in the central nervous system (with neural cells and stem cells from nasal olfactory mucosa); ii) molecular therapy using agents that control the action of matrix metalloproteinases, neuroinflammation, leukocyte recruitment, axonal regeneration; iii) innovative vectorization strategies for addressing drugs and imaging agents to the central nervous system (CNS) through the blood-brain barrier (BBB).

Pictures from the INP laboratory

Research teams

All INP teams are affiliated to the neuroscience master’s program and can thus train neuroscience master’s students and offer them projects to apply for a Ph.D. scholarship.

BBB and neuroinflammation (Michel Khrestchatisky)

Unlike the vessels of the rest of the body, the BBB is characterized by tight junctions that very effectively regulate the molecular and cellular exchanges between blood and nervous parenchyma. Leukocyte recruitment is an essential step of neuroinflammatory processes associated with many diseases and injuries of the CNS; this recruitment depends on various mediators that modulate locally and possibly transiently the BBB properties to increase or conversely reduce its permeability.
The molecular and cellular mechanisms that regulate the fragility and permeability of the BBB in a neuro-inflammatory context remain poorly understood and are the center of our projects.

We are also interested in family of receptors involved in transport processes across the BBB and we develop vector molecules that bind specifically to these receptors to promote the transport of therapeutic and imaging agents across the BBB. These projects are developed in partnership with the company Vect-Horus (www.vect-horus.com), a spin off from our laboratory.

Members

Michel Khrestchatisky, Philippe Benech, Anne Bernard, Daniel Bertin, Amandine Bonnet, Romy Cohen, Max de Reggi, Sophie Desplat-Jego, Nicolas Gaudin, Bouchra Gharib, Stéphane Girard, Grigorios Kyriatzis, Delphine Stephan, Manuel Van Gijsel Bonnello, Karine Varini. Total : 3 HDRs.

Research axes

  • Effects of the proinflammatory cytokine TWEAK on the properties of the BBB
  • Inhibition of transendothelial migration of inflammatory cells and stimulation of energy metabolism: two facets of a neuroprotective molecule, pantethine
  • Neuromodulation of the BBB permeability; vectorization of molecules across the BBB.

Techniques

  • Molecular biology
  • Biochemistry
  • Cell culture
  • Immunostaining, histology, or flow cytometry
  • Microscopy
  • Animal surgery, stereotaxy
  • Pharmacology
  • Animal behavior

Keywords

Blood-brain barrier, neuro-immune interactions, therapeutic agents, vectorization, neuroinflammation, multiple sclerosis, Alzheimer, transcriptional analysis

Animal cognition and behavior - Disorders of the nervous system - Novel methods and technology development

Neural plasticity and degeneration (Santiago Rivera)

We study the basic mechanisms of neurodegeneration, plasticity and inflammation in the central nervous system, with a projection towards new strategies in neuroprotection and neurorepair. The central topic of the group is the study of the role of matrix metalloproteinases (MMPs) in these processes, in particular in the context of Alzheimer’s disease. We discovered new pro-amyloidogenic and pro-inflammatory roles of some MMPs (i.e. MT-MMPs), suggesting that these proteinases could be new therapeutic targets. We validate these targets and study their mechanisms of action in in vivo and in vitro models of the disease, using molecular and cell biology techniques, biochemistry, functional anatomy, imaging, pharmacology, behaviour and IPS cells from Alzheimer’s patients in collaboration with clinicians and other teams of the laboratory. We also study the impact of neuroinflammation on integrity and dynamics of synapses, and the role played in the regulation of these processes by proteins associated with the cytoskeleton

Members

Santiago Rivera, Kévin Baranger, Amandine Bonnet, Eliane Charrat, Lotfi Ferhat, José Morales Poole Jean-Michel Paumier. Total : 2 HDRs.

Research axes

  • Neurodegenerative diseases, proteinases and neuroinflammation: mechanisms of action and therapeutic validation
  • Inflammation and synapses: role of the cytoskeleton

Techniques

  • Molecular biology
  • Biochemistry
  • Cell culture
  • Immunostaining, histology, flow cytometry
  • Microscopy
  • Pharmacology
  • Animal behavior
  • Brain imaging – Animal

Keywords

Alzheimer, proteinases, amyloid, neuroinflammation, neuronal death cytokines, cytoskeleton, repair, glia, synapse, learning

 

Animal cognition and behavior - Disorders of the nervous system - Excitability, synaptic transmission, network functions

Genes, rhthym and neurophysiopathology (François Féron)

Our team co-discovered and characterised the adult human and rodent nasal olfactory stem cells. We use these unique cells to investigate the molecular mechanisms underlying the symptoms of Autism Spectrum Disorders. An abnormal expression of an enzyme (MOCOS) was unveiled in patients’ stem cells. We now assess the role of this enzyme during brain development and try to identify drugs that restore a physiological expression of MOCOS.

The team also uses human olfactory stem cells for repairing the pathological brain. We performed studies based on the transplantation of olfactory stem cells in models of amnesia and Alzheimer’s disease. We are currently devising new protocols for differentiating stem cells into dopaminergic neurons. The team is engaged in translating our basic research into clinical applications. Trials dedicated to nerve and bone repair are in preparation.

In parallel, in order to improve functional recovery, the team assesses the immuno-modulatory and neurotrophic roles of vitamin D. Preclinical studies on animal models of nerve section, paraplegia and Alzheimer’s disease are encouraging.

Members 

François Féron, Lucile Fievet, Madeleine Garcia, Bruno Gepner, Stéphane Girard, Emmanuelle Lacassagne, Véréna Landel, Maria Morello, Emmanuel Nivet, Pauline Rontani, Gaëlle Guiraudie, Fanny Gaudel. Total : 2 HDRs.

Research axes

  • Olfactory stem cells, a diagnosis tool
  • Olfactory stem cells for cell therapy
  • Vitamin D, a neurosteroid hormone

Techniques

  • Molecular biology
  • Biochemistry
  • Cell culture
  • Immunostaining, histology, flow cytometry
  • Microscopy
  • Animal surgery, stereotaxy
  • Animal behavior
  • Brain imaging – Animal
  • Medical data analysis
  • Bioinformatics

Keywords

Stem cells, olfactory system, plasticity, neurogenesis, cell therapy, vitamin D, autism, Parkinson disease, Alzheimer’s disease, spinal cord trauma

Animal cognition and behavior - Disorders of the nervous system - Excitability, synaptic transmission, network functions - Human cognition and behavior - Sensory systems

Neurobiology of mnesic processes (François Roman)

The team is working on changes in the neurobiological substrate during learning and memory processes, including in pathological conditions. The underlying hypothesis is that durable memory traces proceed from the marking of specific neural networks. These synaptic plasticity mechanisms result from molecular and structural changes that largely remain to be identified and integrated at the behavioral level.

In mice, we developed a new olfactory test, “the tubular olfactory maze” where we test the effect of molecules or genetic manipulations on different memory subcategories. We observed specific structural changes in the dorsal and apical dendrite density of CA1 pyramidal cells of the hippocampus, specifically amplified by a 5-HT4 receptor agonist known for his promnesic effect. We are currently using this test in a model of Alzheimer’s disease (5XFAD transgenic mice).

With the same aim of creating animal models to study memory, we developed a deferred task paradigm in mice that highlights specific deficits as observed in patients with frontal lobe syndrome, including a perseveration behavior.

Finally, with a view to overcome the memory deficits in our amnesic syndrome models in mice, we performed intra-hippocampal transplantation of adult stem cells from the human olfactory mucosa. Following these grafts, we observed a recovery of memory capacity and the ability of these cells to acquire a neural or glial phenotype. We are currently conducting autologous grafts in rat models of amnesia and spinal cord injuries.

Members

François Roman, Guy Escoffier, Evelyne Marchetti-Gauthier, Martine Migliorati, Kévin Sadelli, Elodie Salebert, Gilles Sicard, Jean-Claude Stamegna, Antoine Veron. Total : 3 HDRs.

Research axes

  • Effect of an agonist of 5-HT4 receptors on the dendrite structure of hippocampal neurons
  • Memory performance in a model of Alzheimer’s disease (5XFAD transgenic mice) in a tubular olfactory labyrinth
  • Deferred task tests in a mouse model of frontal syndrome
  • Autologous transplants of adult stem cells in rats with amnesia or spinal cord injuries.

Techniques

  • Molecular biology
  • Biochemistry
  • Cell culture
  • Immunostaining, histology, flow cytometry
  • Microscopy
  • Electrophysiology (in vivo)
  • Animal surgery, stereotaxy
  • Pharmacology
  • Animal behavior
  • Psychophysical tests
  • Brain imaging – Animal

Keywords

Synaptic plasticity, learning, memory, 5HT4 receptors, mnemonic disorders, transplantation, olfactory stem cells, Alzheimer’s disease, frontal disorders, spinal cord injuries

Animal cognition and behavior - Disorders of the nervous system - Excitability, synaptic transmission, network functions - Human cognition and behavior - Sensory systems

Neuro-inflammation and multiple sclerosis (Sophie Desplat-Jégo)

Neurophysiopathology

Stem cells, disease modeling and neuroregeneration (Emmanuel Nivet)

Neurophysiopathology

NeuroCyto: the neuronal cytoskeleton in physiology and disease (Christophe Leterrier)

“NeuroCyto: the neuronal cytoskeleton in physiology and disease” is a lab that started in 2017 and is part of the Neuropathophysiology Institute (INP, CNRS-Aix Marseille University UMR 7051) in beautiful Marseille, France.

The team currently has six members, and we welcome trainees all year long. Motivated students are always welcome to contact us! We aim at building a thriving team to make the best possible science by nurturing openness, exchange, and the excitement of discoveries big and small.

At NeuroCyto, we want to understand how neurons are organized at the cellular level. How do they differentiate, then build and maintain their complex arborization? How do they establish and conserve their polarity, with the axon and dendrites allowing to send and receive signals? Numerous processes contribute to this organization: elaboration of the cell architecture (thanks to the cytoskeleton), protein transport inside the cell (with diffusion and motor proteins), segregation into distinct compartments (such as axon, synapses, dendritic spines…). The NeuroCyto team applies advanced microscopy techniques to directly observe molecular assemblies at the nanoscale in neurons, revealing how they organize the neuron and shape its physiology.

Members

Fanny Boroni-Rueda, Ghislaine Caillol, Angélique Jimenez, Christophe Leterrier, Marie-Jeanne Papandréou. Total : 1 HDR.

Research axes

  • Cell biology of the neuron
  • Axonal cytoskeleton
  • Super-resolution microscopy

Techniques

  • Molecular biology (PCR…)
  •  Biochemistry (Western blot…)
  •  Cell culture
  •  Immunostaining, histology, flow cytometry
  •  Microscopy (fluorescence, confocal, electronic…)

Key words

Neuronal cytoskeleton, axonal, super-resolution microscopy, neuron organization.

Development of the nervous system - Excitability, synaptic transmission, network functions - Novel methods and technology development

Gliomagenesis and microenvironment (Dominique Figarella-Branger)

Our GlioME team develops projects to better understand human glioma biology, to identify new targets, and to evaluate promising anticancer therapies using appropriate cellular and pre-clinical models.

Gliomas are the most common intracranial tumors in humans. The most malignant is glioblastoma (GBM, grade IV), with an incidence of 3–5 out of 100,000 persons in Western countries. GBs are lethal tumors and even optimal surgical resection, followed by chemotherapy and irradiation, results in a median survival of about 12–15 months. We trust that a comprehensive understanding of glioma cell-of origin as well as the intricate micro-environmental landscape of these tumors will result in the development of novel therapeutic strategies.

Therefore, our team focused on:

1. Setting up performing preclinical glioma models and identify new targets

2. Identify glioma biomarkers and participating to clinical trials

We are also involved in basic science consortia dedicated to nanoparticles design and development for brain tumor treatment.

Members

BRAGUER Diane, CHINOT Olivier, ESTEVE Marie-Anne*, FIGARELLA-BRANGER Dominique, HONORE Stéphane, TABOURET Emeline*, TCHOGHANDJIAN-AUPHAN Aurélie*, BAEZA-KALLEE Nathalie, COLIN Carole, CAPPAI Jessica, INTAGLIATA Dominique, MORANDO Philippe, BAKAR Lenaig, TIJERAS Guylaine, BERGES Raphaël, CORREARD Florian, DUMAS NOE, JIGUET-JIGLAIRE Carine, APPAY Romain, PEREZ Thomas, MONTALEYTANG Maeva. Total : 4 HDRs (*+ 3 HDRS in preparation during 2019, one in neuroscience)

Research axes

Fondamental

  • Deciphering the role of A2B5, a cancer stem cell marker, in gliomagenesis
  • Deciphering the role of the Inhibitors of Apoptosis (IAPs) in the regulation of GB progression, microenvironment (angiogenesis, hypoxia and inflammation) and stemness
  • Deciphering the role of Microtubule Dynamics (EB family) in the regulation of GB growth (microenvironment and stemness)

Translationnels : Biomarkers / Therapy

  • Identifying biomarkers for diagnosis, prognosis, response to treatment in gliomas and glioneuronal tumors
  • Deciphering the biological role of MMP2 and MMP9 in GB development and resistance to anti-angiogenic therapies
  • Improving nanoparticle (NPs) delivery in the brain for theranostic applications

Techniques

  • Molecular biology
  •  Biochemistry
  •  Cell culture
  •  Immunostaining, histology, flow cytometry
  •  Microscopy
  • Pharmacology
  • Brain imaging – Animal
  • Medical data analysis
  •  Bioinformatics

Key words

Human gliomas, microenvironment, stem cells, A2B5, IAPs, microtubule dynamics, nanoparticles, diagnostic/prognostic biomarkers, predictive markers of response to treatment, therapeutic targets, preclinical models.

Disorders of the nervous system - Novel methods and technology development

Cytoskeleton and Neurophysiopathology (Hervé Kovacic / Vincent Peyrot)

Neurophysiopathology

Angiogenesis and tumor microenvironment (L'Houcine Ouafik)

Neurophysiopathology

Vect-Horus (Alexandre Tokay / Jamal Temsamani)

Neurophysiopathology

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