MechanoGenetic · Role of mechanical forces in cell-matrix adhesion sites

Cells in our bodies constantly experience mechanical forces from their microenvironment. When cells sense a critical threshold of elevated tension, they hold tight together and allow tissues to function healthily as a group. In certain diseases, however, our cells lose their mechanosensing and adhesive properties and, as a result they get dissociated, as in the case of muscular dystrophies. Integrin-based adhesions to the extracellular matrix (ECM) are emerging as key networks of mechanotransmission. This proposal aims to discover how mechanical forces modulate cell-matrix adhesion at the myotendinous junctions in the developing Drosophila embryo, combining biophysical, molecular and genetic approaches. To achieve this goal, I propose to implement two complementary specific objectives: First, I will identify and quantify the relationship between forces and adhesion strength in mutants affecting either integrin-ECM binding or muscle contractility by utilizing in vivo laser ablation and magnetic tweezers. Second, I will examine whether and how IPP complex -a core module of the integrin adhesome- alters the molecular forces transmitted across Talin, which is a major mechanosensor at integrin junctions, utilizing suitable FRET-based biosensors. Collectively, this interdisciplinary research will provide a novel mechanical framework of how cells integrate forces and maintain tissue integrity in the living organism.Given the striking similarities in the molecular organisation of the myotendinous junctions between fly and human, the outcome of this work will provide a deeper understanding of how we can better combat dystrophic diseases.