University of Edinburgh Momentum Award – Dementias
Lead Research Organisation:
University of Edinburgh
Department Name: UNLISTED
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
Microglia, the resident macrophages of the central nervous system (CNS), and monocyte-derived cells are critical effectors and sculptors of changes in the CNS environment (1). In recent years, it has become clear that microglia and myeloid cells such as monocytes, macrophages, or dendritic cells are ontogenetically and also functionally distinct innate immune cell populations in the CNS. The goal of my research is to characterize the heterogeneity of CNS myeloid cells and to determine their differential functions in neurodegenerative diseases.
Using multiplexed single-cell mass cytometry (CyTOF), we have characterized the phenotypic signature of human microglia, which is distinct from myeloid cells in the cerebrospinal fluid and peripheral blood (2). Notably, we detected significant regional heterogeneity of human microglia. We are currently combining CyTOF with another high-dimensional technique (scRNA-seq) to investigate the context-specific adaptive responses of microglia during pathology. This approach will enable us to identify and characterize previously unknown microglia subsets in the human brain, their spatial distribution, and their changes with aging and neurodegeneration.
In a second line of research, we are establishing a novel CNS-conditioned in vitro model of human microglia using patient-derived induced pluripotent stem cells (iPSCs) in collaboration with Siddharthan Chandran’s group at the DRI. This approach will enable us to study the dynamic changes of microglia that occur in neurodegenerative diseases as a result of genetic mutations and environmental changes. It will also provide us with the opportunity to model the context-specific adaptive responses of microglia that we detect in the human brain, and to explore their potential pathogenetic relevance in neurodegenerative diseases.
We hope that the characterization of disease-associated microglia subtypes in the human CNS will open new avenues for subset-specific therapeutic interventions in neuropsychiatric disorders.
Using multiplexed single-cell mass cytometry (CyTOF), we have characterized the phenotypic signature of human microglia, which is distinct from myeloid cells in the cerebrospinal fluid and peripheral blood (2). Notably, we detected significant regional heterogeneity of human microglia. We are currently combining CyTOF with another high-dimensional technique (scRNA-seq) to investigate the context-specific adaptive responses of microglia during pathology. This approach will enable us to identify and characterize previously unknown microglia subsets in the human brain, their spatial distribution, and their changes with aging and neurodegeneration.
In a second line of research, we are establishing a novel CNS-conditioned in vitro model of human microglia using patient-derived induced pluripotent stem cells (iPSCs) in collaboration with Siddharthan Chandran’s group at the DRI. This approach will enable us to study the dynamic changes of microglia that occur in neurodegenerative diseases as a result of genetic mutations and environmental changes. It will also provide us with the opportunity to model the context-specific adaptive responses of microglia that we detect in the human brain, and to explore their potential pathogenetic relevance in neurodegenerative diseases.
We hope that the characterization of disease-associated microglia subtypes in the human CNS will open new avenues for subset-specific therapeutic interventions in neuropsychiatric disorders.
People |
ORCID iD |
Publications
Böttcher C
(2020)
Single-cell mass cytometry reveals complex myeloid cell composition in active lesions of progressive multiple sclerosis.
in Acta neuropathologica communications
Mueller SH
(2018)
Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.
in Annals of neurology
Valdés Hernández MDC
(2019)
Structural neuroimaging differentiates vulnerability from disease manifestation in colombian families with Huntington's disease.
in Brain and behavior
Nickchen K
(2017)
Reversal learning reveals cognitive deficits and altered prediction error encoding in the ventral striatum in Huntington's disease.
in Brain imaging and behavior
Fernández-Zapata C
(2020)
The use and limitations of single-cell mass cytometry for studying human microglia function.
in Brain pathology (Zurich, Switzerland)
Berchtold D
(2020)
Interaction of microglia with infiltrating immune cells in the different phases of stroke.
in Brain pathology (Zurich, Switzerland)
Fernandez-Klett F
(2020)
Denser brain capillary network with preserved pericytes in Alzheimer's disease.
in Brain pathology (Zurich, Switzerland)
Ormel PR
(2020)
A characterization of the molecular phenotype and inflammatory response of schizophrenia patient-derived microglia-like cells.
in Brain, behavior, and immunity
Prinz M
(2019)
Microglia Biology: One Century of Evolving Concepts.
in Cell
Guideline Title | Chorea Leitlinie |
Description | EHDN |
Geographic Reach | Europe |
Policy Influence Type | Citation in clinical guidelines |
Impact | Treatment guideline for movement disorders |
Description | Neuropsychiatry Committee DGPPN |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Improvement in the services provided for patients with neuropsychiatric disorders, training and education in neuropsychiatry, establishment of national and international treatment guidelines |
Description | Update Neuropsychiatry DGPPN |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Annual workshops for medical care professionals at the DGPPN annual meetings |
Description | BIH Platform Humanized Model Systems |
Amount | € 35,000 (EUR) |
Organisation | Charité - University of Medicine Berlin |
Sector | Academic/University |
Country | Germany |
Start | 01/2019 |
End | 12/2019 |
Description | Peripheral monocytes for central nervous system remyelination |
Amount | £176,629 (GBP) |
Funding ID | C012-19.1 |
Organisation | Multiple Sclerosis Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2020 |
End | 12/2021 |
Description | SFB-TR167 B05,B07,IRTG |
Amount | € 10,600,000 (EUR) |
Organisation | German Research Foundation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 01/2017 |
End | 12/2020 |
Description | CCBS, Prof. Chandran |
Organisation | University of Edinburgh |
Department | Centre for Clinical Brain Sciences (CCBS) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Funding and supervision of PhD student and postdoc, consumables, lab space |
Collaborator Contribution | Funding and supervision of staff, consumables |
Impact | Banerjee et al., submitted for publication Presentations at national conferences |
Start Year | 2017 |
Description | CDBS, Dr. Barry McColl |
Organisation | University of Edinburgh |
Department | Centre for Discovery Brain Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Staff, consumables, expertise |
Collaborator Contribution | Expertise |
Impact | FENS educational symposium 2020 |
Start Year | 2017 |
Description | CDBS, Dr. Dirk Sieger |
Organisation | University of Edinburgh |
Department | Centre for Discovery Brain Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Funding and supervision of staff, consumables, equipment |
Collaborator Contribution | Co-supervision of staff, provision of lab equipment |
Impact | None yet |
Start Year | 2018 |
Description | MRC Center for Regenerative Medicine, Prof. Williams |
Organisation | University of Edinburgh |
Department | MRC Centre for Regenerative Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Co-supervision of PhD student, provision of human biosamples, funding of sequencing costs |
Collaborator Contribution | Lab space, expertise, consumables |
Impact | None yet |
Start Year | 2019 |
Description | Microglia dynamics in CNS regeneration |
Organisation | University of Edinburgh |
Department | MRC Centre for Reproductive Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provision of lab space, animal model and consumables |
Collaborator Contribution | PhD student performed experiments in my lab, established in vitro remyelination assay |
Impact | Lloyd et al., Nat Neuroscience (2019), thesis prize |
Start Year | 2017 |
Description | QMRI, Dr. Miron and Dr. Pridans |
Organisation | University of Edinburgh |
Department | Queen's Medical Research Institute Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Co-supervision of students, funding and supervision of staff, consumables, lab space |
Collaborator Contribution | Co-supervision of students, consumables, lab space |
Impact | Lloyd et al., Nat. Neurosci 2019 Scientific presentations at meetings |
Start Year | 2017 |
Title | EGCG in Huntington"s disease |
Description | Phase 2 randomised, placebo-controlled, multi-centre trial on 1200 mg EGCG/day in patients with Huntington's disease, IIT (DFG funding) |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2015 |
Development Status | Closed |
Clinical Trial? | Yes |
Impact | Pharmacokinetic data in HD patients |
URL | https://clinicaltrials.gov/show/NCT01357681 |
Description | EHDN |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Lead facilitator in Working Group on Symptomatic Treatment and Research |
Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018 |
Description | Extended Board member, DGGPP |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | German Society for Geriatric Psychiatry |
Year(s) Of Engagement Activity | 2019,2020 |
Description | Interview for national news (Spiegel, Welt am Sonntag) |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Explanation of clinical trial results |
Year(s) Of Engagement Activity | 2017,2018 |
Description | Neuropsychiatry Committee DGPPN |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Chair of the Neuropsychiatry Committee, DGPPN |
Year(s) Of Engagement Activity | 2011,2012,2013,2014,2015,2016,2017,2018 |