Projects
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| Name | PHAGO |
|---|---|
| Long Name | Inflammation and AD: modulating microglia function - focussing on TREM2 and CD33 |
| Description | Inflammation and AD: modulating microglia function - focussing on TREM2 and CD33. Clumps of proteins in the brain called amyloid plaques are a hallmark of Alzheimer’s disease, and very often specialised immune cells cluster around these plaques. Recent research has shown that two genes involved in the immune system, TREM2 and CD33, appear to be involved in this immune response to Alzheimer’s disease and could therefore be targets for drugs. However, their exact role in the disease is still poorly understood. The PHAGO project aims to develop tools and methods to study the workings of these genes. The project results will therefore pave the way for the development of novel drugs that could tackle Alzheimer’s disease via this route. |
| Objectives | 1. Bring together scientific knowledge from different technical fields on TREM2 and CD33. 2. Allow rapid transfer of novel academic scientific findings on TREM2 and CD33 and related targets towards pharmaceutical and industrial research use. 3. Acquire key knowledge on the role of TREM2/CD33 in AD, including the development of validated assays, and identification of tool compounds and/or tool antibodies targeted to TREM2/CD33 and related target functions. 4. Generate innovative tools for investigating TREM2/CD33 and related pathways that are suitable for pharmaceutical and industrial research use. 5. Generate new knowledge regarding TREM2/CD33 and neuroinflammation to increase the competitiveness of European SMEs and pharmaceutical companies. 6. Disseminate and enable exploitation of the generated knowledge to relevant stakeholders for further development, including by the creation of a knowledge database containing data generated in this action. |
| Website | https://www.phago.eu/ |
| Start date | 01-11-2016 |
| End date | 01-04-2022 |
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| Name | Projects | Type of institution | Country | |
|---|---|---|---|---|
| Janssen Pharmaceutica NV | EPAD ADAPTED AMYPAD IMPRiND EQIPD NEURONET EMIF IM2PACT PHAGO PRISM RADAR-CNS RADAR-AD ROADMAP IDEA-FAST Pharma-Cog EPND | EFPIA | Belgium | |
| Eli Lilly And Company Ltd | EPAD IMPRiND MOPEAD PHAGO PRISM RADAR-AD ROADMAP NEURONET IDEA-FAST Pharma-Cog | EFPIA | United Kingdom | |
| F. Hoffmann-La Roche AG | EPAD EQIPD EMIF PHAGO PRISM ROADMAP NEURONET IDEA-FAST Pharma-Cog EPND | EFPIA | Switzerland | |
| Sanofi-Aventis Recherche & Developpement | EPAD EQIPD AETIONOMY IM2PACT PHAGO NEURONET Mobilise-D IDEA-FAST EPND | EFPIA | France | |
| H. Lundbeck As | EPAD IMPRiND IM2PACT PD-MitoQUANT PHAGO RADAR-CNS ROADMAP Pharma-Cog | EFPIA | Denmark | |
| Fraunhofer Gesellschaft Zur Foerderung Der Angewandten Forschung EV | EPAD AETIONOMY PHAGO RADAR-AD | Academia | Germany | |
| Abbvie Deutschland GMBH & Co Kg | ADAPTED PHAGO | EFPIA | Germany | |
| Astrazeneca AB | MOPEAD PHAGO Mobilise-D IDEA-FAST PD-MIND Pharma-Cog | EFPIA | Sweden | |
| Orion Oyj | EQIPD PHAGO IDEA-FAST | EFPIA | Finland | |
| Charite - Universitaetsmedizin Berlin | EQIPD PHAGO RADAR-CNS | Academia | Germany | |
| Deutsches Zentrum Fur Neurodegenerative Erkrankungen Ev | IMPRiND PD-MitoQUANT PHAGO EPND | Academia | Germany | |
| Goeteborgs Universitet | PHAGO ROADMAP EMIF EPND | Academia | Sweden | |
| King's College London | PHAGO RADAR-CNS RADAR-AD EMIF PD-MIND EPND | Academia | United Kingdom | |
| Universitaetsklinikum Bonn | AETIONOMY ADAPTED PHAGO | Academia | Germany | |
| University College London | AMYPAD PD-MitoQUANT PHAGO EMIF | Academia | United Kingdom | |
| University Of Cambridge | EPAD IMPRiND PHAGO EMIF IDEA-FAST | Academia | United Kingdom | |
| Arttic | PHAGO | SME | France | |
| Axxam SA | PHAGO | SME | Italy | |
| Life And Brain Gmbh | PHAGO | SME | Germany | |
| Eisai Inc | EPAD PHAGO Pharma-Cog | EFPIA | United States |
| WP number | Description | Project | |
|---|---|---|---|
| WP1 | Project management, communication and dissemination | PHAGO | |
| WP2 | Pathways, ligands, signaling | PHAGO | |
| WP3 | In vitro and in vivo models of AD-related neuro-inflammation | PHAGO | |
| WP4 | Identification of small and/or large molecule modulators | PHAGO | |
| WP5 | Data and knowledge management | PHAGO |
| Deliverable number | Title | Project | Submission date | Link | Keywords | |
|---|---|---|---|---|---|---|
| D5.1 | A comprehensive roadmap for data and knowledge management for the PHAGO consortium, collection of pre-existing ethical documents | PHAGO | 27-04-2017 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5b86d2ed0&appId=PPGMS | ||
| D2.8 | Knowledge of possible disease mechanisms and targets | PHAGO | 21-01-2020 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5cb4ffd2c&appId=PPGMS | ||
| D4.6 | Crystal structure of CD33 generated to ~3 Å and refined to ~2 Å | PHAGO | 19-12-2019 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5ca8658cf&appId=PPGMS | ||
| D2.13 | Determination of the cleavage site | PHAGO | 27-01-2017 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5bac10253&appId=PPGMS | ||
| D1.1 | Press release containing a common part and a part that can be personalised by every partner | PHAGO | 11-01-2017 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5b86053f2&appId=PPGMS | ||
| D1.2 | Launch of website, Twitter and other dissemination activities | PHAGO | 19-04-2017 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5b86d256b&appId=PPGMS | ||
| D2.21 | CD33 receptor ligands characterization in human primary monocytes | PHAGO | 09-01-2020 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5caeda5fd&appId=PPGMS | ||
| D3.13 | Providing existing RNAseq signatures and cytokine/chemokine signatures of microglia from tg4510 (tau) mice at various time points | PHAGO | 04-10-2017 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5b86d2d70&appId=PPGMS | ||
| D2.26 | Completion of the analysis of changes in the glycosylation of TREM2 ectodomains in the presence of R47H variant | PHAGO | 19-11-2018 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5c13c9e53&appId=PPGMS | ||
| D2.28 | map the cleavage sites on TREM2 ectodomains in the presence/absence of the R47H variant | PHAGO | 11-02-2020 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5cc009eda&appId=PPGMS | ||
| D4.05 | Crystal structure of TREM2 generated to at least 2-3 Å | PHAGO | 04-03-2020 | https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5ccba80dd&appId=PPGMS |
| Title | First author last name | Year | Project | Link | Keywords | |
|---|---|---|---|---|---|---|
| TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant | Thornton | 2017 | PHAGO | http://doi.org/10.15252/emmm.201707673 | Basic science research paper, TREM2, Alzheimer's disease, inflammation, myeloid cells | |
| An Alzheimer associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function | Schlepckow | 2017 | PHAGO | https://doi.org/10.15252/emmm.201707672 | Basic science research paper, TREM2, inflammation, microglia, Alzheimer's disease | |
| Loss of Trem2 in microglia leads to widespread disruption of cell co-expression networks in mouse brain | Carbajosa | 2018 | PHAGO | https://doi.org/10.1016/j.neurobiolaging.2018.04.019 | Basic science research paper, TREM2, Alzheimer's disease, inflammation, RNA-Seq, Knockout mouse model, Endothelial cells | |
| Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis | Garcia-Reitboeck | 2018 | PHAGO | https://doi.org/10.1016/j.celrep.2018.07.094 | Basic science research paper, induced pluripotent stem cells (iPSC), microglia, TREM2, phagocytosis, inflammation, Nasu-Hakola disease, Alzheimer disease | |
| The Trem2 R47H Alzheimer’s risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans | Xiang | 2018 | PHAGO | https://doi.org/10.1186/s13024-018-0280-6 | Basic science research paper, clinical research, Alzheimer’s disease, Microglia, inflammation, Neurodegeneration, TREM2, Pre-mRNA splicing, microglia | |
| Effective Knockdown of Gene Expression in Primary Microglia With siRNA and Magnetic Nanoparticles Without Cell Death or Inflammation | Carrillo-Jimenez | 2018 | PHAGO | https://doi.org/10.3389/fncel.2018.00313 | Basic science research paper, microglia, inflammation, siRNA, transfection, TREM2, CD33, Alzheimer’s disease | |
| Loss of Function of TREM2 Results in Cytoskeletal Malfunction in Microglia | Phillips | 2018 | PHAGO | https://dx.doi.org/10.16966/2379-7150.152 | Basic science research paper, inflammation, microglia, Nasu-Hakola disease, Dementia, TREM2 | |
| Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE | Parhizkar | 2019 | PHAGO | https://doi.org/10.1038/s41593-018-0296-9 | Basic science research paper, TREM2, ApoE, Amyloid, Alzheimer's disease, mouse model, PET imaging | |
| TREM2 triggers microglial density and age-related neuronal loss | Linnartz-Gerlach | 2019 | PHAGO | https://doi.org/10.1002/glia.23563 | Basic science research paper, TREM2, microglia, inflammation, mouse model, aging | |
| Small Molecule Binding to Alzheimer’s Risk Factor CD33 Promotes Aβ Phagocytosis | Luke | 2019 | PHAGO | https://doi.org/10.1016/j.isci.2019.07.023 | Basic science research paper, CD33, amyloid, Alzheimer's disease, inflammation | |
| Enhancing Protective Microglial Activities With a Dual Function TREM2 Antibody to the Stalk Region | Schlepckow | 2020 | PHAGO | https://pubmed.ncbi.nlm.nih.gov/32154671/ | Basic research paper, Alzheimer's disease, TREM2, amyloid β-peptide, microglia, therapeutic antibody | |
| Lipopolysaccharide activates microglia via neuraminidase 1 desialylation of Toll‐like Receptor 4 | Allendorf | 2020 | PHAGO | https://doi.org/10.1111/jnc.15024 | Basic research paper, microglia, inflammation, in vitro, sialic acid | |
| A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia | Piers | 2019 | PHAGO | https://doi.org/10.1096/fj.201902447R | Alzheimer´s disease, glycolysis, metabolism, microglia | |
| A rare heterozygous TREM2 coding variant identifiedin familial clustering of dementia affects an intrinsicallydisordered protein region and function of TREM2 | Karsak | 2019 | PHAGO | https://doi.org/10.1002/humu.23904 | Alzheimer´s disease, conformation, dementia, intrinsically disordered region, TREM2 | |
| Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease | Boza-Serrano | 2019 | PHAGO | https://doi.org/10.1007/s00401-019-02013-z | Alzheimer’s disease (AD), Galectin-3, TREM2, Microglia, Inflammation, Amyloid aggregation | |
| Sialylation acts as a checkpoint for innate immune responses in the central nervous system | Klaus | 2020 | PHAGO | https://doi.org/10.1002/glia.23945 | complement system, desialylation, microglia, neuraminidases, sialic acid, SIGLEC | |
| Sialylation and Galectin-3 in Microglia-Mediated Neuroinflammation and Neurodegeneration | Puigdellívol | 2020 | PHAGO | https://doi.org/10.3389/fncel.2020.00162 | sialic acid, desialylation, galectin-3, phagocytosis, microglia, neurodegeneration, aging | |
| Interleukin‐12/23 deficiency differentially affects pathology in male and female Alzheimer's disease‐like mice | Eede | 2020 | PHAGO | https://doi.org/10.15252/embr.201948530 | Alzheimer's disease, gender, IL‐12/IL‐23, innate immunity, β‐amyloid, | |
| Plasma levels of soluble TREM2 and neurofilament light chain in TREM2 rare variant carriers | Ashton | 2018 | PHAGO | https://doi.org/10.1186/s13195-019-0545-5 | Alzheimer’s disease, sTREM2, Blood, Biomarkers, Neurofilament light chain | |
| Activated microglia desialylate their surface, stimulating complement receptor 3‐mediated phagocytosis of neurons | Allendorf | 2019 | PHAGO | https://doi.org/10.1002/glia.2375 | complement receptor 3, desialylation, inflammation, microglia, neuraminidase, neurodegeneration, phagocytosis, | |
| Deletion of Alzheimer's disease-associated CD33 results in an inflammatory human microglia phenotype | Wißfeld | 2021 | PHAGO | https://doi.org/10.1002/glia.23968 | Alzheimer's disease, CD33 (sialic-acid-binding immunoglobulin-like lectin 3 [SIGLEC3]), microglia, neuroinflammation, oxidative burst, phagocytosis, protein tyrosine phosphatase, non-receptor type 6 (PTPN6) | |
| Reporter cell assay for human CD33 validated by specific antibodies and human iPSC-derived microglia | Wißfeld | 2021 | PHAGO | https://doi.org/10.1038/s41598-021-92434-2 | antibody, cell, phosphorylation, signaling, calcium, receptor, activation | |
| Differential interaction with TREM2 modulates microglial uptake of modified Aβ species | Joshi | 2021 | PHAGO | https://doi.org/10.1002/glia.24077 | Alzheimer's disease; FTD mutation; TREM2; amyloid β; phosphorylation; post-translational modification. | |
| TREM2 modulates differential deposition of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits | Joshi | 2021 | PHAGO | https://doi.org/10.1186/s40478-021-01263-x | TREM2, Microglia, Post-translational modification, Aβ, Intraneuronal, Vascular deposits | |
| Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons | Mallach | 2021 | PHAGO | https://doi.org/10.3390/cells10112866 | Alzheimer’s disease; dementia; exosomes; intercellular signalling; microglia; proteome. | |
| A reporter cell system for the triggering receptor expressed on myeloid cells 2 reveals differential effects of disease-associated variants on receptor signaling | Ibach | 2020 | PHAGO | https://doi.org/10.1002/glia.23953 | TREM2 variants; agonistic antibody; reporter system; signaling. | |
| Microglial phagocytosis of neurons in neurodegeneration, and its regulation | Butler | 2021 | PHAGO | https://doi.org/10.1111/jnc.15327 | Alzheimer's disease; Parkinson's disease; ageing; microglia; neurodegeneration; neuroinflammation; phagocytosis. | |
| CD33M inhibits microglial phagocytosis, migration and proliferation, but the Alzheimer’s disease-protective variant CD33m stimulates phagocytosis and proliferation, and inhibits adhesion | Butler | 2021 | PHAGO | https://doi.org/10.1111/jnc.15349 | Alzheimer's disease; CD33; Microglia; Neuroinflammation; Siglec-3. | |
| Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation | Vilalta | 2021 | PHAGO | https://doi.org/10.1016/j.jbc.2021.100631 | Alzheimer's disease; TREM2; amyloid beta; microglia; neurotoxicity; oligomers; sTREM2. | |
| The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles | Mallach | 2021 | PHAGO | https://doi.org/10.1093/braincomms/fcab009 | Alzheimer’s disease; TREM2; exosomes; microglia. |
| Title | Description | Type | Project | |
|---|---|---|---|---|
| Neuroimaging data from the KCL neuroimaging study | PHAGO will perform prospective human clinical Positron Emission Tomography (PET) scanning of neuroinflammation in a very small group (MMSE=20) with/ without TREM2 R47H alleles (at KCL). For more information please visit: |
dataset-clinical-phago-12 | PHAGO | |
| CSF samples from the TREM2 variant cohort of KCL | PHAGO will search for novel microglia related biomarkers in the CSF of AD patients using advanced mass spectrometry technologies for allowing a better monitoring of potential therapies. Samples will be obtained from participants in the TREM2 variant cohort (R47H) at KCL. For more information please visit: |
biological-samples-clinical-phago-7 | PHAGO | |
| Biomedical Knowledge Miner from Fraunhofer | The Biomedical Knowledge Miner (BiK>Mi) provides tools to access and validate knowledge encompassing all of the latest information pertaining to Alzheimer's Disease. This project aims to use a comprehensive computational model of biological mechanisms in the context of Alzheimer's Disease to determine currently used drugs that can effectively treat this disease. This drug repurposing workflow would significantly expedite development and research time as well as be applied to a variety of diseases. |
platform-non-clinical-phago-12 | PHAGO | |
| Tools and assays for targeting and analysing TREM2 & CD33 | PHAGO will generate TREM2 and CD33 tools for use to the research community. These tools will include reporter cells and optimised reporter assays, suitable for further development of treatments targeting TREM2 and/or CD33 in AD. Furthermore, PHAGO will generate several iPSC lines with TREM2 and CD33 variants. For more information, please see: |
tools-non-clinical-phago-15 | PHAGO | |
| TREM2 cleavage modulators and uses thereof | This asset relates to a binding molecule having a binding site within the ectodomain of the triggering receptor expressed on myeloid cells 2 (TREM2), wherein the binding molecule inhibits TREM2 cleavage. This binding molecule is particularly useful for treating and/or preventing a neurological disorder, such as a neurodegenerative disorder. Also encompassed by this asset is a pharmaceutical composition for use in treating and/or preventing a neurological disorder, wherein the pharmaceutical composition comprises the binding molecule of the asset. Neurodegenerative disorders that may be treated and/or prevented by using the binding molecule of this asset include Alzheimer's disease (AD), Frontotemporal lobar degeneration (FTLD), FTLD-like syndrome, Parkinson's disease, Nasu-Hakola disease, Multiple sclerosis (MS), Huntington disease, immune-mediated neuropathies, or Amyotrophic lateral sclerosis (ALS). https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018015573 |
tools-non-clinical-phago-29 | PHAGO |
| Website: https://www.phago.eu/ |
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