Academisch Medisch Centrum Universiteit van Amsterdam

Research focuses on proteins of the P4 ATPase subfamily of the P-type ATPase superfamily. P4 ATPases are implicated in the transport of phospholipids within membranes. Intramembranous lipid transport is essential for normal regulated cell function. For instance, maintenance of the asymmetric distribution of phospholipids within membrane bilayers is crucial for proper membrane (protein) function. Secondly, concentrating specific phospholipids in one hemileaflet of the bilayer (i.e. dissipating the non-random distribution of phospholipids) is important for e.g. activation of blood coagulation and engulfment of apoptotic cells, but also in the biogenesis of transport vesicles. Studies in yeast indicate that P4 ATPases play a pivotal role in the biogenesis of intracellular transport vesicles, polarized protein transport and protein maturation. In mammals, 14 P4 ATPases are expressed of which the cellular and physiological functions are largely unexplored. Using an ATP8B1-deficient mouse model, we have extensively studied the (patho)physiology ATP8B1, the P4 ATPase that is impaired in patients with inherited forms of intrahepatic cholestasis (PFIC1 and BRIC1). One of the research plans is to study the pathophysiology of these diseases in more detail using a mouse model with a predisposition to cholestatic liver disease. This mouse model is obtained by crossing ATP8B1-deficient mice with liver-specific P450 reductase knockout mice. The double transgenic mice are not able to synthesize/detoxify bile salts. By feeding these mice ‘human’ bile salts we will render a mouse model with a humanized bile salt pool which is far more toxic than that of the mouse itself. The second objective is to study the cellular and physiological functions of P4 ATPases and their ß-subunits in hepatic and intestinal epithelial cells. We will knock-down all P4 ATPases present in these cells and analyze these cells for endo-, exo, and transcytosis phenotypes. In addition, we will study the role of several of these proteins in vivo. This research will benefit our knowledge on the cellular and physiological importance of these proteins and will help to identify yet unknown P4 ATPase-associated diseases.