Project description
A closer look at flies flexing their muscles
Although water accounts for more than half a body's mass, the cells are not free-floating in all this milieu of extracellular space. In fact, the extracellular matrix (ECM) present in all tissues and organs provides essential physical scaffolding for the cells and is responsible for many biochemical and biomechanical cues required for tissue formation, cell differentiation and homeostasis. Integrins are a family of proteins that attach a cell’s cytoskeleton to the ECM and other cells and sense adhesion. Remarkably, they can sense and transmit information across the junctions bidirectionally. Disruption of integrin function likely plays a role in some diseases. The EU-funded MechanoGenetic project will investigate the role of integrin in mediating mechanical forces at a muscle-tendon junction in flies for insight into human muscular dystrophies.
Objective
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.
Fields of science
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensorsbiosensors
- medical and health sciencesbasic medicineneurologymuscular dystrophies
- medical and health sciencesclinical medicineembryology
- natural sciencesphysical sciencesopticslaser physics
Keywords
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
115 27 Athina
Greece