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Deciphering SENsing Of membrane satuRation with functional genetics (SENSOR)

Project description

Universal assay to study the saturation of cell membrane fatty acids

Living cells control the biophysical properties of their lipid membranes via membrane fluidity and fatty acid (FA) saturation. Our understanding of the regulation of membrane fluidity and the dynamic balance between unsaturated FAs and saturated FAs in the membrane is hampered by the lack of experimental methods to trace FA saturation at a tempo-spatial resolution in live cells. The EU-funded SENSOR project aims to enhance understanding of the regulation of FA metabolism via establishing a universal cellular system to follow membrane saturation in mammalian cells using an innovative fluorescent-based reporter. The researchers will identify the genetic traits that determine membrane saturation, applying state-of-the-art genome-wide CRISPR/Cas9-based assays.

Objective

All living cells must control the biophysical properties of their lipid membranes. Accordingly, dysregulation of the mechanisms underlying this process is associated with a wide range of human diseases, including amongst others metabolic disorders and cancer. In recent years, the role of fatty acid (FA) saturation in controlling membrane fluidity has gained great attention given the realization that the balance between unsaturated fatty acids (UFAs) and saturated fatty acids (SFAs) in the membrane is dynamic, and can be regulated to meet cellular needs. Herein, the SREBP-1 and -2 transcription factors play a pivotal role owing to their ability to control the level of cholesterol and fatty acid saturation.

Our ability to understand the regulation of membrane fluidity and the intimate interaction between this property and SREBP regulation is hampered by the lack of experimental methods to faithfully follow FA saturation in a tempo-spatial resolution in live cells. To address this gap and to advance the field beyond the current state-of-the-art I therefore propose to combine my expertise in advanced functional genetic approaches with that of Prof. Zelcer in the molecular regulation of lipid metabolism, and specifically aim to:

1) Establish a universal and widely-applicable cellular system that reports on ER membrane saturation in mammalian cells through the use of an innovative fluorescent-based reporter.
2) Determine the genetic traits that govern ER membrane saturation in an unbiased manner with state-of-the-art genome-wide CRISPR/Cas9-based assays.

The proposed experiments will greatly enhance our understanding of the regulation of FA metabolism and will result in the generation of innovative and widely applicable experimental tools for in vitro and in vivo monitoring of membrane saturation. These studies may also inform on novel therapeutic strategies to treat lipid-associated disorders.

Coordinator

ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Net EU contribution
€ 175 572,48
Address
MEIBERGDREEF 15
1105AZ Amsterdam
Netherlands

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Region
West-Nederland Noord-Holland Groot-Amsterdam
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 175 572,48