Molecular Mechanisms of Sterol Export from the Lysosome
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Bjørn Panyella Pedersen
Institution
Aarhus University
Beløb
DKK 4,499,599
År
2019
Bevillingstype
Semper Ardens: Accelerate
Hvad?
The focus of the project is on cholesterol uptake in the cell. Universally, the first cholesterol uptake step in cells is the endocytosis of lipid droplets into degradative organelles called lysosomes. Cholesterol is integrated into the lysosomal membrane by the Niemann-Pick type C (NPC) system and then reshuffled to other cellular membranes by cytosolic Lipid Transfer Proteins (LTP). Cholesterol homeostasis using these systems are not understood, and we will address cholesterol homeostasis and shuttling from a structural perspective.
Hvorfor?
Too much blood cholesterol is one of the main causes of cardiovascular disease. Cholesterol is an important component of all cells and needed to facilitate many cellular functions in the body. Cholesterol uptake is mediated by the NPC system. In addition, filovirus infection (eg. Ebola virus) is dependent on this elusive process. Therefore, studies on cholesterol uptake by the NPC system are of great interest, as more knowledge about the uptake has a direct impact on many aspects of lipid research and metabolic research.
Hvordan?
We will address cholesterol uptake by the NPC-system using a complementary set of methods founded in macromolecular crystallography and electron microscopy to determine the 3-dimensional structures of key players in this uptake system. This will be followed up by biochemical characterization of the molecular mechanism in vitro and in vivo.