Description de la soumission d'un avis
The PhD project below is part of NeuroSchool’s “MD-PhD Scholarships” call, which will fund 1 scholarship among the 3 proposed projects.
APPLICATION MUST PROCEED THROUGH OUR WEBSITE: https://neuro-marseille.org/en/Calls/md-phd-scholarships/
STATE OF THE ART : Traumatic brain injury (TBI) is a major public health problem. It is amongst the leading causes of mortality in young people, and many survivors of TBI suffer from persistent disabilities. As a result, there remains an unmet clinical need for the development of more robust diagnostic and prognostic indicators of TBI. Biomarkers can be any quantifiable product serving as a marker of physiopathological state of a subject at a certain time point or disease state (Strathmann.F et al, 2018). They can indicate health, pathology, or response to treatment, including unwanted side effects. Blood biomarkers are valuable tools for elucidating complex cellular and molecular mechanisms underlying traumatic brain injury. Profiling distinct classes of biomarkers could aid in the identification and characterization of initial injury and secondary pathological processes (Battista. A et al, 2015). Biomarkers, to assess neurological involvement, should be objective, inexpensive, easily accessible, noninvasive tools to monitor the course of infection and identify those at risk for neurological damage. While cerebrospinal fluid (CSF) is thought to be closest to the neuropathology, it is an invasive procedure, and like blood, will have a complex protein profile comprised of different cell types. Exosomes are 30–150 nm microvesicles formed in late endosomes and collected as multivesicular bodies prior to fusion with the plasma membrane. They are shed from various cells under normal as well as pathological conditions into the surrounding milieu including plasma, urine, saliva and inflammatory tissues. The cellular cargo packaged into exosomes can be significantly altered depending on the physiological state of the parent cell including immune activation (Sun.B et al, 2018). Most cells in the (CNS) nervous system including neurons, astrocytes, oligodendrocytes and microglia shed exosomes (Review Gupta.A et al, 2014). These extracellular vesicles are secreted by neural cells under normal and pathological conditions and have been isolated from the CSF, adult human brain and recently plasma. Exosomes can reflect the host cell proteins and nucleic acids at the time of secretion, and can be taken up by recipient cells thereby altering their function and setting off a cascade of events that alter homeostasis (lynn.P et al, 2018). Exosomes can diffuse across the blood brain barrier (BBB) into the periphery and be captured by antibodies directed against the cell surface proteins embedded in the vesicle membrane. This strategy has been used to isolate neuron-derived exosomes (NDE) (Mustapic.M et al, 2017).
OBJECTIVES: In this project, our goal is to identify and characterize the diagnostic and prognostic performance of blood biomarkers that reflect specific pathogenic mechanisms including neuroinflammation, oxidative damage, and neuroregeneration, and to use circulating neuronal derived exosomes as a new source of biomarkers.
METHODS: Our approach combines a biochemical study by analysis of candidate proteins by western blot and an RNAseq analysis to target on a large scale the constitution of circulating cerebral exosomes.
EXPECTED RESULTS: Thus, the expected results will be to confirm a specific isolation method of neuronal derived exosomes combined with rapid detection of proteins (western blot, proteomics) or miRNA (Q-PCR), and to go through a first validation step for candidate biomarkers useful for the early detection of post-traumatic disorders (primary screening, first hours) and for the evaluation of the disease (severity, functional consequences) also for early assessment of response to therapeutic agents.
FEASIBILITY: The feasibility of the project is good, the murine model of trauma is used routinely in the team, the institute is fully equipped to conduct all of the studies and the staff of the team trained in all the approaches necessary to the success of this project.Nature de finanement
The first two years of the project, our student learnt the needed technology and abilities that allowed us to detect some of our candidate markers of interest in biological samples. In the third year we will try to characterize the fluctuation of those candidates in TBI context.