PhD in cell biology and Immunology (M/F)

Job Description

Thesis Subject

Juvenile dermatomyositis is an autoimmune disease characterized by inflammatory involvement of the skin and muscles, associated with vasculopathy. It is the most common inflammatory myopathy in children, and it is associated with significant morbidity and mortality (2%). Its pathophysiology is still only partially understood, but increased IFN-1 signaling is typically found in the blood and affected tissues. IFN-I plays a well-defined role in antiviral innate immunity and epidemiological studies showed that JDM is regularly preceded by symptoms consistent with infections. Viral infections are common in children within the age range of JDM, so the occurrence of disease suggests the existence of intrinsic predisposition factors. However, there is currently no report of familial recurrence nor Mendelian inheritance in JDM, indicating that the presumed genetic susceptibility is not sufficient by itself to trigger the disease.
First-line treatments (corticosteroids and methotrexate) induce complete or partial remission in fewer than half of patients. Yet the use of JAK inhibitors as second-line therapy, targeting the IFN-1 pathway, has shown efficacy in 2/3 of refractory patients in recent studies. Furthermore, juvenile dermatomyositis displays considerable clinical and prognostic heterogeneity, which is also observed in the muscular alterations seen on histological examination of biopsies. Therefore, our working hypothesis is that JDM results from the occurrence of an uncontrolled IFN-I driven inflammatory response, triggered by viral infection in predisposed children. In muscle tissue, myopathological changes are associated with a multifocal capillary loss, muscle ischaemia and perifascicular myofibre atrophy. The individual sensitivity of muscle resident cells to IFN-I related inflammation could be a key factor determining disease progression. A better understanding of this aspect of disease will pave the way for the identification of novel targeted treatment.
Our main objective is to improve our understanding of the mechanisms leading to disease onset and progression in JDM. We will:
• Characterize the molecular and cellular mechanisms of the link between RNA viral infection and disease onset by
• Characterize in affected tissues, the mechanisms driving vasculopathy and associated muscle damage.
We will build upon our novel findings from recent years, to: i) clarify the molecular and cellular mechanisms underlying the uncontrolled activation of RNA sensor signalling pathways and associated IFN-I production in JDM patients. ii) generate and characterise to our knowledge the first iPSC-derived endothelial cells from JDM patients. iii) define in coculture experiments the behaviour of muscle resident cells from patients and controls to IFN-I related stress. iv) Better understand the chronology of the pathophysiological mechanism in the muscle leading to capillary loss and muscle atrophy.

Your Work Environment

Located in the heart of Paris at the Centre Universitaire des Saints Pères of the University Paris Cité, the Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCPBT, UMR8601) is a CNRS–Paris Cité joint research unit conducting research at the interface between chemistry and life sciences.. The team BIOLOGICAL CHEMISTRY is a multidisciplinary team composed of chemists, biochemists and immunologist who share common strategies related to protein chemistry and reactivity. Its activity involves chemical synthesis, protein chemistry, redox (bio)chemistry, molecular modelling, metabolism, studies on the reactivity and biological functions of metabolites or effector molecules and their impact on cellular function. The team is organized into 4 interconnected thematic groups with shared technical support staff members.

Constraints and risks

Aucun

Compensation and benefits

Compensation

2300 € gross monthly

Annual leave and RTT

44 jours

Remote Working practice and compensation

Pratique et indemnisation du TT

Transport

Prise en charge à 75% du coût et forfait mobilité durable jusqu’à 300€

About the offer

About the CNRS

The CNRS is a major player in fundamental research on a global scale. The CNRS is the only French organization active in all scientific fields. Its unique position as a multi-specialist allows it to bring together different disciplines to address the most important challenges of the contemporary world, in connection with the actors of change.

CNRS

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