Failure of liver functioning affects millions of people around the world. Despite of this and its known ability to regenerate itself, surprisingly little is understood about the mechanisms guiding both liver regeneration and functioning. A key element in providing liver functionality is the presence of specific cells in the tissue, but also their correct arrangement there. This distinct microarchitecture relies on the correct polarization of cells, e.g. the hepatocytes. The hepatocyte polarization involves the formation of several restricted apical domains per cell, which together create the bile canalicular (BC) network, an essential component for bile secretion and overall liver function. This peculiar structure is currently collecting increasing attention as comprehension of these events will help to understand conditions that cause liver diseases.
As actin remodelling and contraction has been associated with both generation of polarity and organ development, this project will address how actin-based contraction and specific actin-scaffolding/regulating proteins affect the formation of hepatocyte apical domains and BC. Using RNAi and inhibition of the activity of specific proteins (e.g. myosin), confocal microscopy and accompanying high-thoughput image analysis this project aims at identifying key proteins of the actin machinery (e.g. scaffolding and contraction) required for the formation of hepatocyte polarity and the characteristic BC network both in vitro and in vivo. This study will describe how specific molecular components of the actin machinery affect the mechanisms of tissue generation and function, bridging the molecular and cell biology data with the anatomy and physiology of the liver organ. Furthermore, these data will be used by the host collaborators in the Virtual Liver Network project for the development of a large-scale model describing liver functioning from subcellular to tissue to organ levels, which may become clinically relevant.
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