Work package 2

Pathways, ligands, signaling

 

In Work package 2 (WP2) PHAGO will identify targets in the TREM2 and CD33-signalling microglial pathway, elucidate the receptor ligands and determine the functional role of CD33 and TREM2-related targets in phagocyte signalling.

The first aim of WP2 is to: i) identify novel AD risk genes within microglial pathways, ii) identify downstream genes/pathways with altered expression by TREM2, CD33 and their variants, and iii) compare the mouse and human TREM2/CD33 pathways in disease and animal model systems. This pathway analysis will help to identify druggable points of intervention and possible potential side effects within the TREM2 and CD33 pathways.

 

The second aim of WP2 is to identify possible sugar, lipid and protein ligands of TREM2 and CD33 to better understand receptor function and to allow generation of possible agonists/antagonists.

Neural structure

Neural structure
(image: KCL)

The third aim of WP2 is to characterize TREM2 and CD33 metabolism/ signalling, and thereby to identify druggable entry points for regulation of TREM2 and CD33. Therefore, we will: 1) establish robust assays of TREM2- and CD33-dependent intracellular signalling, phagocytic activity and migration, 2) characterize TREM2- and CD33-dependent intracellular signalling pathways, and 3) test if and how TREM2- and CD33-dependent signalling interact to regulate microglia/macrophage functions.
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This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies.

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This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies.