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Cytoskeletal force generation and force transduction of migrating leukocytes

Objective

Cell migration is a universal feature of all metazoan life and crucially involved in most developmental, homeostatic and pathological processes. Most efforts to understand its molecular and mechanical aspects were focused on the “haptokinetic” paradigm. Here cells generate traction by coupling the protrusive and contractile forces of the actomyosin cytoskeleton via transmembrane receptors to the extracellular environment. Our recent work demonstrated that leukocytes, the class of animal cells that migrates with highest speed and efficiency, violate this paradigm. Once embedded in physiological three-dimensional matrices they instantaneously shift between adhesive and non-adhesive modes to transduce force. This proposal suggests a combined cell biological and biophysical approach to elucidate the molecular and mechanical principles underlying such plasticity. We will focus on the machinery most proximate to force generation and use genetics and pharmacology to characterize how nucleation, elongation, depolymerization and crosslinking of actin filaments act in leukocytes migrating through environments of varying geometry and adhesive properties (Postdoc 1). Mechanical manipulations in conjunction with high resolution monitoring of substrate deformations will reveal how cytoskeletal force is transduced to the extracellular environment (Postdoc 2). In a technical support project (Technician) we will develop a cell-system with optimized access to stable genetic manipulations. Technically, these questions will be addressed by employing advanced live cell fluorescence imaging in combination with artificial environments engineered using microfluidics and substrate micropatterning. Importantly, findings will ultimately be challenged in living tissues. This multidisciplinary approach will generate an integrated view of locomotion-plasticity that will not only impact basic cell biology and immunology but also developmental and cancer biology.

Call for proposal

ERC-2011-StG_20101109
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Host institution

INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
Address
Am Campus 1
3400 Klosterneuburg
Austria
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 458 125
Principal investigator
Michael Sixt (Dr.)
Administrative Contact
Carla Mazuheli-Chibidziura (Ms.)

Beneficiaries (1)

INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
Austria
EU contribution
€ 1 458 125
Address
Am Campus 1
3400 Klosterneuburg
Activity type
Higher or Secondary Education Establishments
Principal investigator
Michael Sixt (Dr.)
Administrative Contact
Carla Mazuheli-Chibidziura (Ms.)