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Theses

Identification d'ARNs non-codants impliqués dans les dystrophinopathies

Abstract : Duchenne (DMD) and Becker (BMD) muscular dystrophies are due to mutations in DMD gene, encoding Dystrophin. Many aspects of pathophysiological mechanisms of these diseases are not yet well understood. We were interested in the study of non-coding RNAs that could be involved in these pathological processes. A first study focused on micro-RNAs (miRNAs) that could modulate expression of the neuronal nitric oxide synthase (nNOS), a partner of Dystrophin which is linked to pathological features as muscular fatigability. 617 miRNAs were screened by Taqman Low Density Array in muscle biopsies of healthy subjects or BMDdel45-55 patients. 4 candidate miRNAs were selected from this study since they were overexpressed in BMDdel45-55 patients and for their theoretical ability to target nNOS. Experiments modulating the expression of these miRNAs in healthy or dystrophic human myoblasts enabled us to identify that miR-708-5p and miR-34-5p could target nNOS and modulate its expression.A second axis was conducted on long non-coding RNA (lncRNA). Introns 44 and 55, which bound exons 45-55 deleted in BMDdel45-55 patients, are large regions containing lncRNAs described as regulating Dystrophin. Since intronic breakpoints of DMD mutations of these pateints were not described, we have assumed the existence of different profiles of lncRNAs. DNA analysis of these patients actually showed different lncRNAs profiles, thus revealing the significance of a more precise analysis of deletion areas in DMD gene of BMDdel45-55 patients.
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Marine Guilbaud. Identification d'ARNs non-codants impliqués dans les dystrophinopathies. Biologie cellulaire. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS042⟩. ⟨tel-02121057⟩

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