Towards an in vivo functional dissection of the role of microglia and macrophages in Alzheimer’s disease aetiology

Lead Research Organisation: Cardiff University

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

In vivo study of microglia/MØ function is essential to understand how alterations in basic physiological processes, mostly implicated by the genetics of disease (from cell signalling, endocytosis and phagocytosis, lysosomal functions, adhesion and migration, proliferation and renewal), contribute to dysfunctions that may predispose to disease. The in vivo context is essential for the study of MØ phenotype (discussed below), provides a bridge between cell culture and 3d models and human disease, and importantly is amenable to study of disease alterations and testing of potential therapeutic interventions. A collaboration has been established with Gareth Howell (GH) at the Jackson Laboratories (Honorary Cardiff Senior Research Fellow), who has a large US National Institute of Ageing-funded AD model generation programme. Based on Prof. Williams’ observations, GH introduced the protective SNP from PLCG2 into the corresponding highly conserved sequenced in mouse Plcg2 using CRISPR technologies in C57BL/6 mice. The fertility of these mice has been confirmed and they should be shipped to Cardiff in Q2 of 2017. Our collaboration places us in a strong position to rapidly move from identification of novel disease associated variants (Prof. Williams’ ongoing independent genetic discovery programme) to generation of novel mouse models for in vivo dissection of their mechanistic role in diseases susceptibility or protection.

Publications

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Bart VMT (2021) Macrophage reprogramming for therapy. in Immunology

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Griffiths JS (2021) A Human Dectin-2 Deficiency Associated With Invasive Aspergillosis. in The Journal of infectious diseases

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Griffiths JS (2018) Differential susceptibility of Dectin-1 isoforms to functional inactivation by neutrophil and fungal proteases. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

 
Description 3Rs initiative
Geographic Reach Europe 
Policy Influence Type Contribution to new or Improved professional practice
 
Description A framework for the use human iPSC-derived microglial cultures in translational platforms.
Amount £249,875 (GBP)
Organisation UK Dementia Research Institute 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2022 
End 01/2025
 
Description ARUK platform seedcorn
Amount £4,400 (GBP)
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 08/2018
 
Description GeoMx Digital Spatial Profiler and nCounter
Amount £444,188 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2022 
End 01/2025
 
Description Hodge Centre PhD Studentship
Amount £80,000 (GBP)
Organisation The Jane Hodge Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2017 
End 09/2020
 
Description Hodge Centre Project Grant
Amount £25,000 (GBP)
Organisation The Jane Hodge Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 08/2018
 
Description Hodge Centre Seedcorn
Amount £5,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom
Start 06/2017 
End 08/2018
 
Description IMPC pump prime award
Amount £24,024 (GBP)
Funding ID MR/P024939/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2016 
End 11/2018
 
Description IPSC Platform to Model Alzheimer's disease Risk (IPMAR)
Amount £1,866,149 (GBP)
Organisation UK Dementia Research Institute 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2020 
End 02/2022
 
Description MRC DTP Studentship
Amount £80,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 03/2021
 
Description PhD studentship
Amount £90,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom
Start 09/2019 
End 09/2022
 
Description Understanding microglial dysfunction in Alzheimer's disease through rare coding variants.
Amount £219,375 (GBP)
Organisation UK Dementia Research Institute 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2021 
End 09/2024
 
Description World Class Laboratories Capital Equipment
Amount £248,025 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2020 
End 07/2023
 
Description 2Pmicro 
Organisation International University Of Catalonia
Country Spain 
Sector Academic/University 
PI Contribution We are conducting the experiments with our reagents
Collaborator Contribution Intellectual input and software modification. External to UKDRI.
Impact New research experimental approach has opened to us. Involves in vivo 2-photon imaging.
Start Year 2018
 
Description BPM_NA_BS 
Organisation Cardiff University
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution intellectual and as required expert laboratory assistance
Collaborator Contribution lead and laboratory research and expertise
Impact too soon.
Start Year 2017
 
Description Behave 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution We are conducting the experiments with our reagents.
Collaborator Contribution Intellectual oversight and instruction. External to UKDRI.
Impact Skills transfer to our team (behavioural science)
Start Year 2019
 
Description CB 
Organisation Helmholtz Association of German Research Centres
Department The Max Delbrück Center for Molecular Medicine (MDC)
Country Germany 
Sector Academic/University 
PI Contribution We are leading this research, designing the study and utilizing a model created at the MDC, by CB.
Collaborator Contribution They provided a model, which we have merged with ours for our study.
Impact Data from this collaboration has gone towards supporting further funding application to MRC UK Dementia Research Institute.
Start Year 2017
 
Description EiCollabPD 
Organisation Eisai Ltd
Department Eisai Europe Ltd
Country United Kingdom 
Sector Private 
PI Contribution We are leading and conducting a research project in collaboration with an industrial partner
Collaborator Contribution Financial support and possibility of exploitation.
Impact N/A
Start Year 2021
 
Description GM_RS_ELE 
Organisation Cardiff University
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Providing staff member to conduct research and leading on reagent provision.
Collaborator Contribution Intellectual and specialist technical.
Impact Resulted in journal publication.
Start Year 2018
 
Description P2micro2 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution We conduct the experiments and provide the unique reagents.
Collaborator Contribution Providing intellectual input. External to UKDRI.
Impact Skills transfer in in vivo 2-photon imaging.
Start Year 2019
 
Description WG_BPM_NW 
Organisation Cardiff University
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution contribution is intellectual and laboratory based.
Collaborator Contribution They lead and conduct laboratory research.
Impact The collaboration has just begun and new techniques required have begun.
Start Year 2017
 
Description WG_NI_RA 
Organisation Cardiff University
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Lead this small collaboration. Establishing new technology base in Cardiff.
Collaborator Contribution Intellectual and practical expertise
Impact This collaboration is ongoing. We have the new technique established and SOPs written and are confirming a bioinformatics pipeline to accompany it.
Start Year 2017
 
Description YS_AH 
Organisation Cardiff University
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution intellectual input
Collaborator Contribution lead and laboratory work.
Impact too soon
Start Year 2017
 
Description iPSC 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution functional assays of provided cells to provide insight into cell signalling pathways
Collaborator Contribution They provide mutated human iPSC to translate our studies in mouse models. External to UKDRI.
Impact Contribution of reagents to publication in process.
Start Year 2018
 
Description iPSCvalid 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input and experimental collaboration
Collaborator Contribution Intellectual input and experimental collaboration
Impact N/A
Start Year 2021
 
Description ARopen 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact One of the team spoke at a charity sponsored open day for the public
Year(s) Of Engagement Activity 2019
 
Description Brain Games 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Held in the national museum, this is a science outreach to the general public, focused on neuroscience
Year(s) Of Engagement Activity 2018
 
Description DRpod 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Two science discussion podcasts
Year(s) Of Engagement Activity 2020
 
Description Day event for the public on Alzheimer's Disease 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was a public event for the launch of the Dementia Research Institute in Cardiff. The emphasis on this event was engagement with the public. I performed short, repeating 'soapbox' style presentation on an aspect of understanding Alzheimer's Disease.
Year(s) Of Engagement Activity 2018
 
Description ExpDay 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Research experience day for potential students wishing to engage with research practice
Year(s) Of Engagement Activity 2019