Frédéric RELAIX
IMRB Team 10 - Biology of the neuromuscular system
IMRB Team 10 - Biology of the neuromuscular system
KEYWORDS: Skeletal muscle progenitors and stem cells
Mouse molecular genetics
Skeletal muscle stem cells specification, muscle regeneration, regulation of growth arrest
Environmental stress, muscle stem cell niche
Mouse molecular genetics
Skeletal muscle stem cells specification, muscle regeneration, regulation of growth arrest
Environmental stress, muscle stem cell niche
Neuromuscular diseases (NMDs) form a large group of heterogeneous disorders affecting the different levels of the skeletal muscle functional unit from the peripheral nerve control to the musculoskeletal effector, with particular emphasis put on neuromuscular diseases causing muscular degeneration. Often untreatable, and in many cases very disabling or lethal, they pose a variety of challenges regarding scientific knowledge, preclinical modelling, therapeutic approaches and public health.
The primary objective of our project is to capitalize on the complementary expertise in basic, translational, preclinical and clinical research of our large team, organized as complementary groups working on the neuromuscular system, with a exclusive continuum from strong biology-centred basic science to physiopathological research, generation of new models and tools, cohort studies, and therapeutic assays.
Our project is structured in two main interdependent axis:
The first workpackage is focusing on skeletal muscle stem cells. We will specifically investigate PAX3 and PAX7 myogenic transcription factors functions linked with downstream gene regulatory networks and transcriptional regulation during development and in adult stem cells, as well as their potential role in NMDs. We are also interested in the molecular regulation of postnatal stem cells specification, growth arrest and quiescence, as well as in the cellular and molecular components of their niche and local environment, notably signalling of the microvascular unit, regulation of quiescence by Notch, and the interaction with environmental stress. These basic studies will stimulate the development of new translational approaches, along with tissue engineering for skeletal muscle, biodistribution studies and therapeutic studies, including the use of skeletal stem cells for biotherapy. Our outstanding expertise in the field complemented with our privileged access to human tissues and cell cultures will be instrumental for these studies.
The second workpackage is focusing on translational approaches for molecular medicine. By combining our expertise with onsite access to patients and by favoring within-team interactions of scientists with veterinarians and clinicians, we are interested in NMDs pathophysiology, identification of susceptibility factors, development of evaluative tools and biomarker studies for a set of NMD including inflammatory/dysimmune myopathies, centronuclear myopathies (CNMs) and congenital myopathies with fiber size disproportion, Duchenne Muscular Dystrophy and myotonic dystrophies. Complementary studies will involve the specific development of targeted biotherapy development (i.e. pharmaceutical approach and antisense oligonucleotide therapies) for CNMs and other NMDs of interest. Clinical trials are complex and very expensive, and most are failing due to the lack of solid preclinical studies. Components of our team have been pioneers and are worlds experts in large animal modelling for NMDs. We will therefore further develop our preclinical studies in CNMs and GRMDs dog models, including cell therapies, gene therapies and pharmaceutical approaches. A strong transversal objective for our team is to establish novel and accurate preclinical models for neuromuscular diseases, in particular large animal models. For ethical reasons, a sequential approach will be set up which will promote the use of spontaneous models, already or to be characterized at the clinical and molecular levels. In some very specific, highly-evaluated situations, newly-generated models will be established by genome editing in pigs or dogs. Finally, access to onsite hospital structure and facilities will likewise allow us to perform clinical trials, such as initiated for dysferlinopathies.
The innovative structuration of our team, as a set of complementary groups that include a broad spectrum of models and expertise, offers a unique strategic position with a continuum combining basic, translational, preclinical and clinical research. We therefore believe that our combination of expertise and facilities united in a coherent and highly collaborative effort offers a unique structure to achieve this highly ambitious research program on neuromuscular diseases.
The primary objective of our project is to capitalize on the complementary expertise in basic, translational, preclinical and clinical research of our large team, organized as complementary groups working on the neuromuscular system, with a exclusive continuum from strong biology-centred basic science to physiopathological research, generation of new models and tools, cohort studies, and therapeutic assays.
Our project is structured in two main interdependent axis:
The first workpackage is focusing on skeletal muscle stem cells. We will specifically investigate PAX3 and PAX7 myogenic transcription factors functions linked with downstream gene regulatory networks and transcriptional regulation during development and in adult stem cells, as well as their potential role in NMDs. We are also interested in the molecular regulation of postnatal stem cells specification, growth arrest and quiescence, as well as in the cellular and molecular components of their niche and local environment, notably signalling of the microvascular unit, regulation of quiescence by Notch, and the interaction with environmental stress. These basic studies will stimulate the development of new translational approaches, along with tissue engineering for skeletal muscle, biodistribution studies and therapeutic studies, including the use of skeletal stem cells for biotherapy. Our outstanding expertise in the field complemented with our privileged access to human tissues and cell cultures will be instrumental for these studies.
The second workpackage is focusing on translational approaches for molecular medicine. By combining our expertise with onsite access to patients and by favoring within-team interactions of scientists with veterinarians and clinicians, we are interested in NMDs pathophysiology, identification of susceptibility factors, development of evaluative tools and biomarker studies for a set of NMD including inflammatory/dysimmune myopathies, centronuclear myopathies (CNMs) and congenital myopathies with fiber size disproportion, Duchenne Muscular Dystrophy and myotonic dystrophies. Complementary studies will involve the specific development of targeted biotherapy development (i.e. pharmaceutical approach and antisense oligonucleotide therapies) for CNMs and other NMDs of interest. Clinical trials are complex and very expensive, and most are failing due to the lack of solid preclinical studies. Components of our team have been pioneers and are worlds experts in large animal modelling for NMDs. We will therefore further develop our preclinical studies in CNMs and GRMDs dog models, including cell therapies, gene therapies and pharmaceutical approaches. A strong transversal objective for our team is to establish novel and accurate preclinical models for neuromuscular diseases, in particular large animal models. For ethical reasons, a sequential approach will be set up which will promote the use of spontaneous models, already or to be characterized at the clinical and molecular levels. In some very specific, highly-evaluated situations, newly-generated models will be established by genome editing in pigs or dogs. Finally, access to onsite hospital structure and facilities will likewise allow us to perform clinical trials, such as initiated for dysferlinopathies.
The innovative structuration of our team, as a set of complementary groups that include a broad spectrum of models and expertise, offers a unique strategic position with a continuum combining basic, translational, preclinical and clinical research. We therefore believe that our combination of expertise and facilities united in a coherent and highly collaborative effort offers a unique structure to achieve this highly ambitious research program on neuromuscular diseases.
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