Summary
Lipid flippases mediate transport of phospholipids from the exoplasmic leaflet to the cytosolic one, and their role is to establish and maintain phospholipid asymmetry in eukaryotic membranes. This asymmetry is tightly regulated and it is implicated in numerous cellular processes such as membrane trafficking, signaling, blood coagulation, apoptosis, cytokinesis, or cell fusion. The human genome encodes 14 different P4-ATPases, a subset of them being linked to pathologies such as mental retardation, Alzheimer’s disease, diabetes, cancer or liver disorders. As concerns the latter disease, it has been demonstrated that mutations of the human lipid flippase ATP8B1, are responsible for inherited intrahepatic cholestasis. The intrahepatic cholestasis affects mostly children and is characterized by pruritus, recurrent jaundice, growth failure and an evolutive liver degradation which requires transplantation before adulthood in most severe cases. Up to now, little is known about the function of ATP8B1 at the canalicular membrane and this is mainly due to the lack of consensus regarding its transport substrate and how its activity is regulated. Preliminary results indicate that ATP8B1 has a broader transport substrate specificity than previously reported in the literature and therefore its study will widen our understanding of the biochemical basis of lipid selectivity in lipid flippases. In addition, in the proposed project I aim at understanding how a disease related lipid flippase, ATP8B1, is regulated in vitro and in vivo and at understanding functional and structural consequences of identified mutations of ATP8B1 linked to the intrahepatic cholestasis.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/101024542 |
| Start date: | 01-03-2021 |
| End date: | 28-02-2023 |
| Total budget - Public funding: | 219 312,00 Euro - 219 312,00 Euro |
Cordis data
Original description
Lipid flippases mediate transport of phospholipids from the exoplasmic leaflet to the cytosolic one, and their role is to establish and maintain phospholipid asymmetry in eukaryotic membranes. This asymmetry is tightly regulated and it is implicated in numerous cellular processes such as membrane trafficking, signaling, blood coagulation, apoptosis, cytokinesis, or cell fusion. The human genome encodes 14 different P4-ATPases, a subset of them being linked to pathologies such as mental retardation, Alzheimer’s disease, diabetes, cancer or liver disorders. As concerns the latter disease, it has been demonstrated that mutations of the human lipid flippase ATP8B1, are responsible for inherited intrahepatic cholestasis. The intrahepatic cholestasis affects mostly children and is characterized by pruritus, recurrent jaundice, growth failure and an evolutive liver degradation which requires transplantation before adulthood in most severe cases. Up to now, little is known about the function of ATP8B1 at the canalicular membrane and this is mainly due to the lack of consensus regarding its transport substrate and how its activity is regulated. Preliminary results indicate that ATP8B1 has a broader transport substrate specificity than previously reported in the literature and therefore its study will widen our understanding of the biochemical basis of lipid selectivity in lipid flippases. In addition, in the proposed project I aim at understanding how a disease related lipid flippase, ATP8B1, is regulated in vitro and in vivo and at understanding functional and structural consequences of identified mutations of ATP8B1 linked to the intrahepatic cholestasis.Status
CLOSEDCall topic
MSCA-IF-2020Update Date
28-04-2024
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