Project description
Rewiring signalling to find therapy for SEPN1-related myopathy
Selenoprotein-related myopathy (SEPN1-RM) is a rare untreatable congenital myopathy in which SEPN1 mutations impair the antioxidant system and mitochondrial oxidative function, leading to a significant loss of bioenergetic production and muscle cell functions, potentially lethal respiratory failure and mobility impairment. The EU-funded REBOOST project aims to use patient-derived cells to establish high-throughput readouts of metabolism, facilitating drug repurposing for SEPN1-RM, and employ original treatment strategies exploiting signallings bypassing SEPN1 defects to restore cellular bioenergetics. This study will facilitate the establishment of SEPN1-RM biomarkers and novel therapeutic studies, and provide a model approach for the analysis and treatment of other inherited or acquired myopathies sharing an underlying bioenergetic deficiency, including sarcopenia and cancer cachexia.
Objective
SEPN1-related myopathy (SEPN1-RM) is a rare, untreatable debilitating congenital myopathy in which SEPN1 mutations impair the antioxidant system, ER stress protection and mitochondrial oxidative function. These altered cellular processes ultimately lead to a significant loss of bioenergetic production and abrogate muscle cellular functions. SEPN1-RM patients experience potentially-lethal respiratory failure and major life burden due to loss of mobility. Currently, there are no high-throughput or appropriate preclinical models to facilitate identification of disease-modifying drugs; this has hampered efforts in devising therapeutic strategies. To overcome these bottlenecks, I aim to use patient-derived cells to establish (1) high-throughput measureable readouts of metabolism, facilitating repurposed drug screen for SEPN1-RM; (2) an original treatment strategy by exploiting potential biased signalings, which bypass SEPN1 defects to restore cellular bioenergetics. I will capitalize on (1) the availability of SEPN1-RM biopsies, (2) host lab expertise for handling and culturing primary SEPN1-RM cells and (3) my experience in muscle biology and innovative tools for analysing metabolic/signalling pathways. I aim to implement transcriptomic analyses by using next-generation RNA-seq, optogenetic based sensors to quantify metabolic activity, real-time clonal analysis of cell fate with dynamic fluorescent time-lapse microscopy and multi-dimensional assessment of intracellular activities at single-cell level via CYTOF technology. This study will not only facilitate the establishment of SEPN1-RM biomarkers and novel therapeutic studies, it will also provide a model paradigm for analysing and treating other inherited or acquired myopathies sharing an underlying bioenergetic deficiency, including sarcopenia and cancer cachexia.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciencesphysical sciencesopticsmicroscopy
- natural sciencesbiological sciencesgeneticsmutation
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensors
- medical and health sciencesclinical medicineoncology
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Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
75006 Paris
France