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MOLECULAR BIOMARKERS FOR EARLY DIAGNOSTIC OF RADIATION INJURY – CAESAR

Submission summary

In the event of a radiological or nuclear emergency following an accident or malicious act, potentially involving a large number of victims, the medical management requires the identification and diagnosis of both military and civilian populations exposed to high doses of ionizing radiation (IR) in a timely manner.
Feedback from clinicians at HIA Percy and the needs identified by the IAEA-IEC indicate the need to develop new diagnostic and prognostic tools for radiological burns. Indeed, the reference treatment, based on the injection of autologous stem cells associated with reconstructive surgery guided by dosimetric reconstruction, remains complex to implement in case of a radiological or nuclear emergency involving a large number of potential victims. Therefore, the early detection of the most severely exposed victims to IR would allow them to be treated as a priority in order to benefit rapidly from an appropriate therapy (e.g. stem cell injection), compared to individuals irradiated at lower doses, and thus less at risk, as well as to unexposed persons present during the incident.
The objective of the CAESAR project is to identify, through a global omics approach, new non-invasive biological indicators, for diagnostic and predictive purposes, of the risk of occurrence and severity of a radiological burn, using a preclinical mouse model of localized radiation injury.
This project is based on the expertise of the different partners in the fields of clinical management of radiological burns and omics analysis. We will use a preclinical model established in the laboratory, in which the hind limb of male and female mice is exposed to different doses of IR, leading to the development of radiation burns of different severity grades. Blood and urine samples will be collected 24 hours (acute phase) and 7 days (asymptomatic latency) after irradiation, i.e. before the appearance of clinical signs.
The expression profiles of the microRNAs (miRNAs) will be generated using dedicated commercial panels (qPCR). Metabolomic and lipidomic analyses will be conducted by ultra-high-performance chromatography coupled to mass spectrometry. Non-invasive measurements will be performed on the animals at regular intervals in order to follow the evolution of the lesion: observational injury score, skin microcirculation (laser Doppler), skin barrier function (Tewameter). Broad-spectrum molecular signatures will be generated by means of multivariate statistical analyses, allowing the development of mathematical models predictive of the risk of appearance and the degree of severity of the lesions. Targeted analyses of the selected miRNAs and metabolites will be performed on independent cohorts of male and female animals, in order to consolidate the mathematical models and validate the selected predictive biomarkers.
This project has a strong dual character, because the discovery of new molecular markers for early diagnosis, before the onset of symptoms, would allow the rapid identification and triage of soldiers in operation, or civilians in the context of a malicious act, exposed to IR and likely to develop a radiation-induced injury and requiring medical treatment, in a radiological emergency situation. The targeted molecules (miRNA, metabolites) are compatible with the molecular diagnostic tools routinely used in medical analysis laboratories, thus allowing their potential clinical transfer. In addition, these biological indicators could be used in the medical field to monitor the effectiveness of applied treatments or to identify patients likely to develop adverse effects in situations of controlled use of IR (radiotherapy, interventional radiology).

Project coordination

Maâmar SOUIDI (IRSN - Pôle Santé Environnement - Direction Santé)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

C2VN Aix Marseille Université
IRSN/PSE-SANTE IRSN - Pôle Santé Environnement - Direction Santé

Help of the ANR 299,622 euros
Beginning and duration of the scientific project: - 36 Months

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