Dissecting macroglial-neuronal crosstalk in C9ORF72 Frontotemporal dementia/ amyotrophic lateral sclerosis
Award Number
UKDRI-4003Programme
Research grantStatus / Stage
ActiveDates
1 September 2017 -31 December 2100
Duration (calculated)
83 years 03 monthsFunder(s)
MRC (UKRI)Funding Amount
£1,536,437.00Funder/Grant study page
MRC UKRIContracted Centre
UK Dementia Research Institute at University of EdinburghPrincipal Investigator
Professor Siddharthan ChandranPI Contact
siddharthan.chandran@ed.ac.ukPI ORCID
0000-0001-6827-1593WHO Catergories
Understanding risk factorsUnderstanding Underlying Disease
Disease Type
Frontotemporal Dementia (FTD)CPEC Review Info
| Reference ID | 248 |
|---|---|
| Researcher | Reside Team |
| Published | 12/06/2023 |
Data
| Award Number | UKDRI-4003 |
|---|---|
| Status / Stage | Active |
| Start Date | 20170901 |
| End Date | 21001231 |
| Duration (calculated) | 83 years 03 months |
| Funder/Grant study page | MRC UKRI |
| Contracted Centre | UK Dementia Research Institute at University of Edinburgh |
| Funding Amount | £1,536,437.00 |
Abstract
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. To reduce dementias and related neurodegenerative disorders (NDD) to merely the consequence of genetic and biochemical dysfunction, invariably from a neuron-centric perspective, is to understate the highly evolved, dynamic and cellular connectedness nature of the human brain. Multiple lines of evidence from pathology, genetics, radiology and experimental systems implicate a central role for glia in (i) not only maintaining (and tuning) neuronal function in health but also, dependent on disease context, being (ii) injurious or (iii) neuroprotective1. Yet the role of macroglia (astrocytes, oligodendrocytes [OLG]) in NDD and ageing, the major risk factor for NDD, is grossly understudied. Dissecting the nature of cellular autonomy and the mechanism of macroglial-mediated influences on neuronal biology and function in health, ageing and NDD requires an integration of diverse experimental approaches. One powerful strategy is the use of human iPS technologies for in vitro as well as, following transplant, longitudinal in vivo study of human glial chimeric mice. This programme will focus on the development and use of mutant (plus gene-corrected isogenic pairs) patient-derived C9orf72 human iPS cells to study NGVU interactions. C9orf72 hexanucleotide G4C2 repeat expansion is an excellent model for studying NGVU cross-talk in NDD because: (i) it is the major genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); (ii) it shares key biological pathways with other NDD; (iii) it underlies a clinical continuum of FTD/ALS with overlapping pathology; and (iv) there is strong evidence for macroglial involvement and non-cell autonomous neurotoxicity in disease pathogenesis
Aims
To reduce dementias and related neurodegenerative disorders (NDD) to merely the consequence of genetic and biochemical dysfunction, invariably from a neuron-centric perspective, is to understate the highly evolved, dynamic and cellular connectedness nature of the human brain.