Project R-11780

Role of the mechanosensitive TRPV4 channel in the continuum of focal adhesions during the migration of microglia. (Research)

Cellular migration is a coordinated process consisting in four sequential steps: cell polarization, protrusion, adhesion to the extracellular matrix and retraction of the extended protrusions. These events 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, we aim at demonstrating that the mechanosensitive calcium-permeable channel TRPV4 is the main contributor to the initial raise in intracellular calcium controlling the establishment, maturation and disassembly of cell adhesions. Using super-resolution microscopy, we will first study the expression pattern and sub-cellular distribution of TRPV4 within the cell adhesion complex. In addition, we will investigate how TRPV4-dependent calcium signaling affects the migratory pattern of microglia, the immune cells of the brain. This will be addressed using state-of-the-art traction force microscopy and tracking of microglia in brain slices. Lastly, we will discern the contribution of TRPV4 in the migration of microglia cells in vivo, using experimental models mimicking acute and chronic brain injury, and microglial migration during brain development. Altogether, this provides a comprehensive approach to mechanosensation during cellular migration.

01 October 2021 - 30 September 2025