University of Edinburgh Momentum Award – Dementias

Lead Research Organisation: University of Edinburgh

Abstract

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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.
 
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 CRG 2a SP6
Amount € 3,020,000 (EUR)
Organisation Berlin Institute for Health Research 
Start 06/2014 
End 12/2018
 
Description SFB-TR167 B05,B07,IRTG
Amount € 10,600,000 (EUR)
Organisation German Research Foundation 
Sector Public
Country Germany
Start 01/2017 
End 12/2020
 
Description Microglia dynamics in CNS regeneration 
Organisation University of Edinburgh
Department MRC Centre for Reproductive Health
Country United Kingdom 
Sector Public 
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 Scientific publication under review
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,
 
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