Blanc SVSE 4 - Blanc - SVSE 4 - Neurosciences

New approaches to monitor and promote myelin repair in animal models of multiple sclerosis – PROMOMY

Understand and promote Myelin regeneration

The lack of tools to characterize in vivo and in vigile animal, the extension of the lesions and remyelination limit the progression of both basic and applied research in the field of demyelinated diseases.

Studying the myelin repair in mice to promote the self-healing process in patients with Multiple Sclerosis

Multiple sclerosis (MS) is a degenerative disease characterized by inflammation and death of oligodendrocytes, cells that produce the myelin sheath, which is essential to the efficient conduction of nerve impulses. Available treatments are designed to limit inflammation but are ineffective against neural cell death and progressive disability of patients. Spontaneous remyelination exists in some patients with MS. Understanding the mechanisms regulating this process of self-repair in mouse models of MS is a prerequisite for the design of new therapies. In this context, our project aims 1) to reveal the cellular and molecular mechanisms underlying the mobilization of endogenous cells to understand and promote self-repair and 2) better characterize in vivo the dynamic of myelin degeneration and regeneration in murine models of MS.

We compared gene expression profiles of neural progenitor from healthy and MS adult mice brains. Doing so, we identified factors upregulated during the regenerative process. We chose to characterize the involvement of two of these genes (netrin-1 and ndst 1) by examining their involvement in the repair process. We will analyze the functional involvement of such factors in the regenerative process and in particular during the migration of progenitors into lesions using a combination of cellular and molecular biology approaches and manipulations of the in vivo expression of these factors in animals. Moreover, we will use brain imaging techniques (MRI/MRS), to dynamically monitor the development of demyelinating lesions and remyelination in different models of MS. The use of these imaging techniques will allow us to obtain new information on inflammation, the state of myelination and axonal loss in the brain, metabolism, and temporal evolution of the disease. The development of such tools will benefit the whole community working on human diseases affecting myelin.

The results of this project show that there is a dialogue between neural progenitors and blood vessels regulating cell mobilization during the regenerative process. We have demonstrated that demyelination induced the formation of new blood vessels and that progenitor cells migrate along these vessels to reach the lesion.
Longitudinal brain MRI studies allowed us to characterize the progressive phase of the disease during which the clinical symptoms appear. Our results suggest that it is possible to follow immune cell infiltration and neuronal suffering in the absence of obvious demyelination in MS mouse model early after disease induction.

This innovative project propose to combine behavioral analysis, brain imaging and histological data on mouse models of MS to establish a link between the appearance of behavioral deficits and disease progression in one hand and myelin regenartion and functional recovery in the other hand.
From a fundamental perspective, this project will help to identify new molecular players involved in demyelination and remyelination in different murine models of MS. These findings could pave the way for the development of new therapies targeting the mobilization of endogenous progenitors.

-Cayre M, Courtés S., Martineau F., Giordano M., Arnaud K. Zamaron A. and Durbec P. Netrin-1 contributes to vascular remodeling in SVZ and promotes progenitor emigration after demyelination. Development (2013) 140, 3107-3117.
El Waly B, Macchi M, Cayre M, Durbec P. Oligodendrogenesis in the normal and pathological central nervous system. Front Neurosci. 2014 Jun 12;8:145. Review.

Multiple sclerosis (MS) is a chronic degenerative and debilitating disease of the central nervous system characterized by inflammation and demyelination. The only current therapeutic option consists in immune modulating treatments which do not allow a complete recovery. Therefore, new therapeutic strategies targeting remyelination are urgently needed. Recent analysis have provided evidence that remyelination can spontaneously occur in some MS patients as well as in animal models of demyelination. Understanding the molecular and cellular mechanisms regulating this self-repair process in rodent models of MS is a prerequisite to design new therapeutic strategies.
Over the past years, we provided the proof of concept that manipulating proliferation, migration and/or differentiation of neural progenitors into oligodendrocytes can be beneficial for myelin repair in mice.
With the aim of expanding this knowledge, we used microarrays experiments and identified several factors whose expression was drastically upregulated in progenitors of demyelinated mice. Among our several candidates, two were of particular interest Netrin1 and ndst1.
Netrin1, a protein described to play a key role in both migration and angiogenesis processes, was consistently found to be upregulated in our chip data. We propose a series of in vivo and in vitro experiments to elucidate the role of Netrin1 in the regulation of the cross-talk between moving progenitors and the newly generated blood vessels upon demyelination.
Ndst1, a key enzyme of heparan sulfate biosynthesis was found to be expressed specifically at the surface of the mobilized progenitor cells around the lesion. With this candidate, we will deeply analyze the implication of extracellular matrix and environmental factors in the repair process.
The second part of our proposed project mainly focuses on developing new and sophisticated paradigms that will allow us correctly monitoring the clinical readouts of the disease onset, progression and repair. Control and diseased mice will be subjected to a battery of behavioral tests by recording their performances to a variety of sensory-motor stimuli at different stages of the disease development. Control and diseased mice will then undergo high resolution imaging techniques followed by histological analyses. Data emanating from these series of experiments will allow one to correlate the performances of mice in the behavioral tests to the degree of myelin repair triggered naturally or upon administration of remyelinating agents.
Our project is twofold: part of it is devoted to increasing our knowledge of the molecular and cellular mechanisms regulating myelin repair and the other part will be devoted to designing measurable paradigms to quantify myelin repair.
Successful outcomes of this project will be of high interest not only to fundamental and medically driven neuroscience but also to the pharmaceutical industry for developing effective compounds to treat/cure multiple sclerosis.

Project coordinator

Madame Pascale Durbec (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE PROVENCE ET CORSE) – pascale.durbec@univ-amu.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CNRS DR 12 _ IBDML CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE PROVENCE ET CORSE
CNRS DR12 _ CRMBM CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE PROVENCE ET CORSE
CNRS DR 12 _ IBDML CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE PROVENCE ET CORSE

Help of the ANR 412,832 euros
Beginning and duration of the scientific project: December 2011 - 36 Months

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