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Til bevillingsoversigt

Molecular Mechanisms of Sterol Export from the Lysosome

Carlsberg Foundation Young Researcher Fellowships

What

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.

Why

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.

How

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.

SSR

High cholesterol cause cardiovascular disease. In addition the NPC mediated cholesterol uptake pathway is an key Ebola virus entry factor, and both are big societal challenges. Future private-public cooperation include improving cholesterol-lowering blockbuster drugs and understanding how to prevent Ebola virus infection.