TRPV4 as a key driver of branch motility and somatic migration of microglial cells (R-9999)

Microglia are the immune cells permanently residing in the central nervous system, where their function is central to maintain proper brain development and health. This crucial role is achieved through an active surveillance process, in which microglia are constantly extending and retracting their multiple branches, or actively migrating to affected areas. Both branch motility and migration are accomplished by the orchestrated assembly and disassembly of protein complexes that attach to the extracellular matrix. Whereas the regulation of these cell adhesions by local intracellular calcium levels is unarguably, the molecular entity and the mechanism leading to the initial calcium influx remains to be defined. In this project proposal, we aim at demonstrating that the mechanosensitive calcium-permeable channel TRPV4 is the main contributor to the initial raise in intracellular calcium. Using super resolution microscopy, we will first study the expression pattern of the channel within the cell adhesion complex and how its activation affects branch motility and migration. In addition, we will investigate how TRPV4- dependent calcium signalling affects the migratory pattern of microglia cells. This will be addressed using state-of-the-art traction force microscopy and tracking of microglia cells in brain slices. Lastly, using experimental models mimicking acute and chronic brain injury, we will discern the contribution of TRPV4 in the migration of microglia cells in vivo.

Keywords:focal adhesions,, microglia, migration,, super-resolution microscopy, TRPV4

Disciplines:Innate immunity, Cell movement, Cell signalling, Neurological and neuromuscular diseases, Cell physiology