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FRINATEK-Fri prosj.st. mat.,naturv.,tek

Mechanochemical interplay in intraluminal vesicle formation

Alternativ tittel: Mekano-kjemisk samspill i formasjonen av intraluminale vesikler

Tildelt: kr 8,4 mill.

I dette prosjektet har vi utviklet en ny forståelse av de mekaniske og biofysiske prosessene som bestemmer dannelsen av membranblåser (vesikler) i cellens indre. Irregulariteter i denne prosessen kan linkes til flere sykdommer deriblant kreft, og denne fascinerende membrandynamikken regulerer cellens interne og eksterne kommunikasjon. Gjennom prosjektet har vi utvikle en presis biofysisk modell som kan forklare denne membran dynamikken, noe vi har utvikle gjennom matematiske modeller og beregningsverktøy i tett samarbeid med eksperimentelle cellebiologer. To kvinnelige forskere er trenet i prosjektet gjennom en PhD stilling og i en post-doc stilling, og vi har etablert et nært samarbeid med eksperimentelle grupper for å teste våre teoretiske modeller.

This multidisciplinary proposal addresses the basic mechanochemical processes that regulate one of the most fundamental communication pathways in cell biology - the encapsulation and internalization of liquid and transmembrane cargo at intracellular membranes. We propose a unique approach by combining classical theoretical methods in mechanics i.e. flow modeling, numerical simulations, with biophysics, in close collaboration with internationally leading experimental biologists (Dr. H. Stenmark, Oslo University Hospital). A master regulator in eukaryotic cell-to-cell communication is the endosome, a membrane bound compartment inside the cell, which encapsulates cargo by forming small-enclosed membrane structures known as Intraluminal Vesicles (ILVs). As these form, they go through a series of mechanical events as membrane associated proteins generate forces that deform the elastic membrane and cause fluid motion. Despite the essential role this process plays in cell signaling, where irregularities are linked to diseases such as cancer, mechanistic models describing ILV formation are scarce and have overlooked the role of viscous flow. Today, advanced microscopy techniques are able to extract a high level of detailed information from the process, which enable development of a precise model. We propose to develop a theoretical platform based on a multiphase flow formalism, which couples; adsorption/desorption of force-generating proteins, elastic membrane deformation and viscous flow, providing a mechanochemical description of ILV formation and the feedback loop that enables robust vesicle formation. Our combination of theory and experiments place us in a unique position to quantify and test predictions of the mechanochemical influence in the dynamics. This will yield novel insight into the biophysical determinants that set the time and length scales of the cargo filled vesicles, which can have implications beyond the fields of bio-physics/mechanics and cell biology

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FRINATEK-Fri prosj.st. mat.,naturv.,tek