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Dr Domercq is currently a research professor at the University of Basque Country, School of Medicine (Spain) and member of the Achucarro Basque Center for Neuroscience.
She received her PhD in neuroscience from the University of the Basque Country (Spain) in 1999, and has worked under the supervision of Dr A Volterra (Institute of Pharmacology in Milan, Italy). In 2011, she became research professor in neuroscience, and currently, Dr Domercq is studying the role of microglia polarization and its possible manipulation by P2X4 receptor signaling in multiple sclerosis (MS) pathology.
Dr Matute is a full professor at the University of Basque Country, School of Medicine (Spain) and Director of the Achucarro Basque Center for Neuroscience.
He received his PhD in medicine from the University of Zaragoza (Spain) in 1982. He has worked under the supervision of Drs M Cuenod and P Streit (Brain Research Institute in Zurich) and Dr R Miledi (University of California in Irvine), working with glial cells. In 2002, he became professor in neuroscience, and has conducted further studies to characterize the process of oligodendrocyte cell death, which could help design strategies to prevent it in neurological disorders, such as MS.
Could re-educating microglia by P2X4 receptor manipulation constitute an alternative therapy for multiple sclerosis?
Microglia survey the central nervous system (CNS) microenvironment for signals of injury or infection. After local damage, the release of adenosine triphosphate (ATP), the main danger signal, induces a beneficial response characterized by microglial migration to the injury site, proliferation, and phagocytosis of cells and debris. However, an excessive and prolonged activation of microglia could be detrimental.
Previous data demonstrate that a microglia polarization switch to M2 cells (alternative macrophages that produce anti-inflammatory cytokines and promote tissue repair and remodeling, as well as tumor progression) is an essential part of the regenerative response in multiple sclerosis (MS). In this context, microglia depletion may not always be necessary in therapy; instead, modulating its activation could offer equally (or even more) effective therapeutic options.
The proposed study will investigate whether re-educating microglia/macrophages, by manipulating P2X4 receptors (P2X4Rs) to eliminate their pro-inflammatory M1 functions and promote their M2 phagocytic and regenerative functions, enhances remyelination in MS. We will characterize the expression and function of P2X4Rs in the CNS and immune cells, and determine the signaling pathways leading to P2X4R+ activated microglial cells.
Consequences on lymphocyte and oligodendroglial functions will be analyzed. Then, we will study the role played by P2X4Rs and the molecular pathways involved in its signalling in MS pathophysiology using different animal models.
Finally, we will investigate if the release or expression of the signaling molecules and receptors correlates with the risk to develop MS or its outcome. We will manipulate the defined pathways with the goal of designing strategies to modulate the human microglia/macrophage polarization state.
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