The role of microRNAs associated with extracellular vesicles in the pathophysiology of multiple sclerosis 

With the support of the Belgian Charcot Foundation, this research project will be undertaken at the neurochemistry laboratory of the Institute of Neuroscience of UCLouvain (IoNS), under the supervision of Professor Vincent van Pesch (IoNS) and Professor Giulio Muccioli (Louvain Drug Research Institute – UCLouvain).

Extracellular vesicles (EVs) enable the transfer between cells of bioactive compounds such as microRNAs, and play a role in many biological processes. The aim of this project is to identify microRNAs from the EVs of multiple-sclerosis (MS) patients according to the stage and level of neuroinflammatory activity of the disease. These microRNAs could play a role in the pathophysiology of the disease by regulating the function of cells involved in neuroinflammation. Their identification and functional characterisation could therefore lead to the uncovering of new therapeutic targets.

Inflammation in multiple sclerosis (MS) involves both hyperactivated peripheral immune cells and resident cells of the nervous system such as astrocytes and microglia. Despite recent advances in the development of disease-modifying therapies (DMTs) designed to reduce the frequency and severity of MS exacerbations, there is still no cure, and their effect on disability progression remains limited. It is therefore essential that new therapeutic strategies be identified.  In this context, the study of bioactive molecules contained in extracellular vehicles (EVs) represents a promising avenue.

EVs are membrane particles secreted by almost all types of cells in our organism and which play a real "cargo" role, allowing the various cells to communicate with each other via the exchange of various mediators (lipids, proteins, nucleic acids, etc.). Among these mediators, this project will focus mainly on vesicular microRNA content. The role of these small RNAs is to block the translation into proteins of the messenger RNAs to which they bind.

Based on the hypothesis that extracellular vesicles contain disease-status-specific microRNAs involved in the regulation of neuroinflammatory processes, their identification would open the way to new therapeutic targets.

This research project comprises three stages:

1. The first part of the project involves isolating extracellular vesicles from the cerebrospinal fluid (obtained by lumbar puncture) of MS patients at different stages of the disease, as well as from healthy patients. Once these extracellular vesicles have been isolated, their microRNA content will be analysed and quantified using various molecular biology techniques.  The chief aim of this first part is therefore to identify the microRNAs, the expression of which is deregulated in the extracellular vesicles circulating in the cerebrospinal fluid of MS patients.   
2. Once these microRNAs that are expressed in different ways depending on the disease status are identified, the second part of the project will focus on studying their functional role. For this purpose, we shall be studying the pro- or anti-inflammatory effect of these microRNAs on two cellular neuroinflammation models, namely astrocytes and microglial cells.
3. The third part of the project will aim to identify the messenger RNA targeted by the microRNA(s) most involved in the regulation of neuroinflammatory pathways.