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Deciphering SENsing Of membrane satuRation with functional genetics (SENSOR)

Descripción del proyecto

Una prueba universal para estudiar la saturación de los ácidos grasos de la membrana celular

Las células controlan las propiedades biofísicas de sus membranas lipídicas a través de la fluidez de sus membranas y la saturación de los ácidos grasos (AG). Nuestra comprensión de la regulación de la fluidez de la membrana y el equilibrio dinámico entre los AG insaturados y los AG saturados en la membrana se ve obstaculizada por la falta de métodos experimentales para rastrear la saturación de los AG a una resolución espaciotemporal en células vivas. El objetivo del proyecto SENSOR, financiado con fondos europeos, es mejorar la comprensión de la regulación del metabolismo de los AG al desarrollar un sistema celular universal para seguir la saturación de la membrana en células de mamíferos mediante un indicador innovador basado en fluorescencia. Los investigadores identificarán los rasgos genéticos que determinan la saturación de la membrana aplicando pruebas hologenómicas de última generación basadas en CRISPR/Cas9.

Objetivo

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.

Coordinador

ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Aportación neta de la UEn
€ 175 572,48
Dirección
MEIBERGDREEF 15
1105AZ Amsterdam
Países Bajos

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Región
West-Nederland Noord-Holland Groot-Amsterdam
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 175 572,48