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Pierre CHAMBON
pierre.chambon@igbmc.fr
Tel. : +33 (0)3 88 65 32 24
Tel. : +33 (0)3 88 65 32 23
Tel. : +33 (0)3 88 65 32 25
Daniel METZGER
daniel.metzger@igbmc.fr
Tel. : +33 (0)3 88 65 34 63
Tel. : +33 (0)3 88 65 34 67

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Identification Of The Molecular And Cellular Events Underlying Prednisolone-Induced Improvements Of Muscle Functions In Duchenne Muscular Dystrophy Patients.

Reference : PhD Daniel METZGER

Offer publication : April 6, 2016

Duchenne muscular dystrophy (DMD) is a lethal X-linked muscle disease, induced by mutation of the dystrophin gene which encodes a protein essential for the maintenance of muscle membrane integrity. The disease is characterized by a progressive muscle weakness of the locomotor, respiratory, cardio-vascular and digestive systems. Glucocorticoids (GC) are the most potent treatment of DMD.

They promote an increase in muscle strength and delay disease progression, but unfortunately do not halt it. Moreover long-term treatments induce various side effects, including osteoporosis, hypertension, obesity and diabetes. Some glucocorticoids (e.g. Prednisolone) have a better benefit/risk balance than others (e.g. Dexamethasone), but the mechanisms underlying their
differential effects are unknown. GC exert highly pleiotropic effects through binding to the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. They are widely
used as treatment of inflammatory and auto-immune diseases. However, their prolonged use is limited by side effects, such as muscular atrophy. As GC have both a positive effect on DMD-patient muscle function and a muscle catabolic activity, identification of the molecular and cellular events induced by GC in skeletal muscles is of major importance to further improve DMD treatment efficacy. Mdx mice, bearing a mutation in the dystrophin gene, exhibit various aspects of the human disease, and thus represent a mouse model of X-linked muscular dystrophy. Prednisolone treatment of mdx mice increases specific force of limb muscles, which might result from decreased inflammation and/or oxidative stress, or increased myofiber differentiation.

Some studies proposed that the benefit of Prednisolone mainly results from immunosuppressive effects on T lymphocytes invading muscles. However, even though various non-steroidal immunosuppressive drugs reduce inflammation in DMD patients, they do not induce muscular improvements as observed with GC, indicating that the primary mechanism of Prednisolone-induced clinical activity is not due to immunosuppressive actions in muscles, and that myofiber GR might importantly contribute to it.

We propose in this project to compare the effects of Dexamethasone and Prednisolone on skeletal muscles of wild-type mice, as well as on mdx mice, to unravel the molecular and cellular events induced selectively by these drugs, and to identify those contributing to DMD clinical improvement, and
those inducing undesired side effects. Networks of genes controlled by Dexamethasone and Prednisolone in skeletal muscle will be determined by analyzing the gene expression profiles, and their direct targets by massive sequencing chromatin immunoprecipitated with an antibody directed against GR. In order to clarify the role of direct GR targets in the regulation of muscle mass, in vivo gain and/or loss of function experiments will be performed in skeletal muscle of mdx mice. In
parallel, a phenotypic analysis of mdx mice in which GR is selectively ablated in muscle cells, will allow to determine the role of GR in the improvement of clinical signs observed in DMD patients treated with Prednisolone.

Thus, this study should allow to identify new drug targets and open new avenues to design potent screens aimed at the identification of drugs that improve DMD treatment.

- WISHED SKILLS : The candidate should have an excellent background in molecular and cellular biology,and in genetics, as well as very good experimental skills and a strong motivation.

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : The training will allow to acquire a large number of cutting-edge approaches and technics, from conditional somatic mutagenesis in the mouse to molecular and cellular analyses. It will also include the organisation of team work,
oral presentations of generated data and writing of grants and publications.

Your application

Application Deadline : Dec. 31, 2016

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