Role of microRNAs in ageing at the blood-brain barrier: integrated studies in human and mouse models
Lead Research Organisation:
University of Sheffield
Department Name: Neurosciences
Abstract
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Technical Summary
The aim of the proposal is to test the hypothesis that age-induced changes in gene expression in cerebral endothelium leading to cerebrovascular dysfunction are mediated, at least partially, by changes in microRNA levels. MicroRNAs (miRs) are endogenous non-coding small RNAs that mediate gene silencing by translation inhibition and/or by mRNA decay of target genes. Evidence suggests a role for miRs in regulating the life span of model organisms but the mechanisms involved in this process are largely unknown. One of the first signs of ageing is the loss of specialized functions by cells. The objective of the work is to elucidate general mechanisms by which miRs may modulate normal ageing in a specialized biological system that is amenable to functional, cellular and molecular investigations, the blood-brain barrier (BBB), across two model organisms with differing life spans, humans and mice. First, we will characterize progressive changes in BBB function in humans and mice during normal ageing. Second, using microarray technology, age-deregulated miRs in the cerebral endothelium and age-associated shifts in the global pattern of target gene expression will be analysed so that changes predicted to be directed by alterations in miR levels at the BBB are identified. Third, specific age-deregulated miRs will be selected using their ability to modulate specialized BBB function and/or known pathways of cellular senescence in vitro. Finally, we will validate actions of specific miRs on putative gene targets and confirm age-induced changes in levels of selected miR/target gene pairs at the BBB. BBB dysfunction is recently emerging as an important factor leading to age-associated loss of homeostasis in the central nervous system and we envisage that age-induced phenotypic changes at the BBB mediated by miRs will be identified that may well be not only specific to cerebrovascular function but also constitute general pathways of ageing across biological systems.
Planned Impact
The proposed research seeks to determine the roles of microRNAs in the endothelium of the blood-brain barrier (BBB) during normal brain ageing. It has two main aims: first to systematically characterise changes occurring in brain endothelial cells during ageing and, second, to identify the roles of microRNAs in these changes, and thus their possible involvement in age-induced BBB dysfunction. Comparison of microRNA changes with alterations in the general endothelial transcriptome will provide a powerful data set of altered endothelial gene expression in ageing. BBB dysfunction and endothelial pathology have been implicated in the development and progression of degenerative brain disease, such as Alzheimer's Disease. However, these processes, their interaction with brain parenchyma ageing and their roles in disease remain poorly defined. The results from the work will therefore have a major impact both on our knowledge base in the areas of microRNA functions, ageing and neuroscience and also in the future, for health and wellbeing, as the results should lead to knowledge that can be used in the development of strategies and therapies to prevent, delay or alleviate age-associated BBB dysfunction in neuropathological conditions. Such novel approaches are essential given the limitations of current strategies.
The immediate beneficiaries of the proposed research are academics, the public sector and third sectors. In the longer term, potential future beneficiaries include health professionals, the commercial private sector and general public.
The academic community will benefit from the proposed research because at present our knowledge of the roles of microRNAs is in its infancy. Evidence suggests that these molecules play a role in ageing and in endothelial cell biology, and the proposed work will provide new information in both these important areas.
Within the public and third sectors, the specific groups to whom this research is relevant are research organisations (including BBSRC, MRC), professional bodies (such as the British Society for Research on Ageing, the British Neuropathological Society and the British Neuroscience Association) and charities (e.g. Age UK, Alzheimer's Research Trust, Alzheimer's Society, Alzheimer's Association). These groups will benefit from the knowledge generated from the project, as it will inform decisions on the future research priorities and development activities in the areas of ageing and neuroscience, in particular neuropathology.
We do not anticipate any early developments that will warrant commercial exploitation, although there is potential for such exploitation in the future. We will ensure that any such developments are taken forward, with appropriate partners and IP procedures.
The health and wellbeing of the general public will benefit from this research in the longer term. For example, understanding how the process of normal ageing affects blood-brain barrier function, in particular that related to transporter activity which influences CNS availability of many commercial drugs, will impact on the development of therapeutic regimes targeted at the ageing population with neurological conditions. The public should also have the benefit of being informed about the work.
The immediate beneficiaries of the proposed research are academics, the public sector and third sectors. In the longer term, potential future beneficiaries include health professionals, the commercial private sector and general public.
The academic community will benefit from the proposed research because at present our knowledge of the roles of microRNAs is in its infancy. Evidence suggests that these molecules play a role in ageing and in endothelial cell biology, and the proposed work will provide new information in both these important areas.
Within the public and third sectors, the specific groups to whom this research is relevant are research organisations (including BBSRC, MRC), professional bodies (such as the British Society for Research on Ageing, the British Neuropathological Society and the British Neuroscience Association) and charities (e.g. Age UK, Alzheimer's Research Trust, Alzheimer's Society, Alzheimer's Association). These groups will benefit from the knowledge generated from the project, as it will inform decisions on the future research priorities and development activities in the areas of ageing and neuroscience, in particular neuropathology.
We do not anticipate any early developments that will warrant commercial exploitation, although there is potential for such exploitation in the future. We will ensure that any such developments are taken forward, with appropriate partners and IP procedures.
The health and wellbeing of the general public will benefit from this research in the longer term. For example, understanding how the process of normal ageing affects blood-brain barrier function, in particular that related to transporter activity which influences CNS availability of many commercial drugs, will impact on the development of therapeutic regimes targeted at the ageing population with neurological conditions. The public should also have the benefit of being informed about the work.
People |
ORCID iD |
Stephen Wharton (Principal Investigator) | |
Paul Heath (Co-Investigator) |
Publications
Al-Mashhadi S
(2014)
Oxidative Glial Cell Damage Associated with White Matter Lesions in the Aging Human Brain
in Brain Pathology
Ameen-Ali KE
(2017)
Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease.
in Neuropathology and applied neurobiology
Garwood CJ
(2017)
Review: Astrocytes in Alzheimer's disease and other age-associated dementias: a supporting player with a central role.
in Neuropathology and applied neurobiology
Goodall E
(2017)
Age-associated changes in the blood-brain barrier: comparative studies in human and mouse
in Neuropathology and Applied Neurobiology
Goodall EF
(2019)
Age-Associated mRNA and miRNA Expression Changes in the Blood-Brain Barrier.
in International journal of molecular sciences
Simpson J
(2015)
Neuronal DNA damage response-associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of A lzheimer-type pathology
in Neuropathology and Applied Neurobiology
Wharton SB
(2015)
Age-associated white matter lesions: the MRC Cognitive Function and Ageing Study.
in Brain pathology (Zurich, Switzerland)
Description | We have now published a paper showing changes in blood brain barrier across age in both humans and mice. We have now completed and published a second paper detailing changes in gene expression in endothelium across the ageing spectrum in humans and comparing this to mice. |
Exploitation Route | It would be good to take forward key pathway targets into functional studies. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | One data paper was published showing that blood brain barrier is increasingly leaky with age in mouse and human. We also published a second paper on gene expression changes. To complete the work for this, we provided a BMedSci student project. This was successfully completed and the student presented at a national conference. |
First Year Of Impact | 2019 |
Sector | Healthcare |
Description | Interdisciplinary research grant |
Amount | £237,984 (GBP) |
Funding ID | ARUK-IRG2014-10 |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2014 |
End | 12/2016 |
Description | Occludin as a Mediator of Neuroglial RNA Dysmetabolism in Dementia |
Amount | £47,703 (GBP) |
Funding ID | ARUK-PPG2019B-005 |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2021 |
End | 10/2021 |
Description | PhD Scholarship |
Amount | £84,450 (GBP) |
Funding ID | ARUK-PhD2016-5 |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2016 |
End | 08/2019 |
Description | Preparatory clinical research fellowship |
Amount | £69,998 (GBP) |
Funding ID | ARUK-PCRF2016A-1 |
Organisation | Alzheimer's Research UK |
Department | Alzheimers Research UK, Cambridge |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2016 |
End | 09/2017 |
Description | Project grant. Basis of post stroke dementia |
Amount | £378,751 (GBP) |
Funding ID | 386 |
Organisation | Alzheimer's Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2018 |
End | 01/2021 |
Title | Development of immuno-directed laser capture microdissection. |
Description | Protocols for cell-type specific laser capture in the CNS. |
Type Of Material | Technology assay or reagent |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | Several papers over the years, most recently brought together in a methods chapter Simpson JE, Wharton SB, Heath PR. Immuno-laser-capture microdissection for the isolation of enriched glial populations from frozen post-mortem human brain. In: Murray G (eds) Laser Capture Microdissection. Methods in Molecular Biology vol 1723; pp273-284, Humana Press, New York, NY |
Title | Age associated endothelial gene expression changes in mouse and human |
Description | Changes in mRNA in endothelium across age span in human brain and mice. Freely available at Gene Expression Omnibus (human array data accession number GSE127710 and mouse array data accession number GSE127709). |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | Availability of data to bioinformatics researchers. |
Description | A Cellular Pathology and Gene Expression Approach to Understand the Basis of Progressive Dementia Occurring After Stroke |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Joint study of post stroke dementia. We will provide laser capture and gene expression analysis. |
Collaborator Contribution | Collaboration has just begun. |
Impact | Just started |
Start Year | 2018 |
Description | Defective nutrient signalling and dementia: an epidemiological neuropathology approach |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Pathological analysis of CFAS tissue studying effects of diabetes on the brain. |
Collaborator Contribution | Tissue analysis. |
Impact | Conference presentations. |
Start Year | 2015 |
Description | Defective nutrient signalling and dementia: an epidemiological neuropathology approach |
Organisation | University of Cambridge |
Department | Cambridge Institute of Public Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Pathological analysis of CFAS tissue studying effects of diabetes on the brain. |
Collaborator Contribution | Tissue analysis. |
Impact | Conference presentations. |
Start Year | 2015 |
Description | Neurovascular dysfunction in Alzheimer's disease: the search for early biomarkers |
Organisation | University of Sheffield |
Department | Department of Psychology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaboration with Psychology bringing together our tissue expertise and linking to physiological analysis. |
Collaborator Contribution | Tissue analysis, laser capture and gene expression microarrays. |
Impact | Review paper detailed in pulications. |
Start Year | 2014 |
Description | ARUK lab tour for lay group. |
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 | Lab tour and talks informing members of public about our research |
Year(s) Of Engagement Activity | 2018 |
Description | Alzheimer Society Local Group Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Member of out group spoke about our dementia research predominantly to dementia support workers. Better public information |
Year(s) Of Engagement Activity | 2014 |
Description | Alzheimer's Society Network Volunteers Visit |
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 | Patients, carers and/or patient groups |
Results and Impact | Visit by lay group. Talks given on the various projects we have underway. |
Year(s) Of Engagement Activity | 2016 |
Description | Alzheimers Research Network Volunteers Visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | Attendance by a group of lay monitors. Presented talks in relation to our projects and lab visit. Opportunities for informal discussion and advice from the lay members. |
Year(s) Of Engagement Activity | 2017 |
Description | Annual meeting of the ARUK Network Yorkshire Branch Open Public Meeting. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Series of talks from members of the Neuroscience Dept in Sheffield and premier of film Alive Inside - documentary about living with dementia. Prof Paul Ince from the Neuropathology group gave a talk about different pathological causes of dementia - to raise awareness of the non-AD types. Public information |
Year(s) Of Engagement Activity | 2014 |
Description | Dementia Futures Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Conference designed to present results on dementia to lay public. 3 of our group's PhD students presented. |
Year(s) Of Engagement Activity | 2018 |
Description | Dementia futures conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Conference to present work of PhD Students to members of the public. Covered by BBC radio Sheffield. Three PhD students from our group gave talks. Also attended by representative of local city council. |
Year(s) Of Engagement Activity | 2019 |
URL | http://tinyurl.com/DementiaFuturesConference2019 |
Description | Dr Garwood presentation at Festival of Science and Engineering Your amazing brain |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Stimulated interest in children Questions |
Year(s) Of Engagement Activity | 2015 |
Description | Invited speaker British Neuroscience Association Symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Generate questions and discussion. Improved professional relationships that might lead to collaboration. Communication both immediately after and by email |
Year(s) Of Engagement Activity | 2015 |
Description | Memory Outreach Clinic |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Discussing our work on dementia with relatives at a local memory café. |
Year(s) Of Engagement Activity | 2020 |
Description | Radio interview by Dr Claire Garwood on our group's work, BBC Radio Sheffield |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Informed public via radio Not formally assessed. |
Year(s) Of Engagement Activity | 2015 |
Description | Research Network volunteer visit (Alz Soc) Aug 2017 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Visit of Alz Soc research network volunteer. Presented the research work of our group. |
Year(s) Of Engagement Activity | 2017 |
Description | SITraN Open Day |
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 | Institute open day with range of talks |
Year(s) Of Engagement Activity | 2018 |
Description | SITraN Open Day July 2014 |
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 | Public/other audiences |
Results and Impact | Open day at SITraN allowing lay persons to look at work on neurodegeneration, in including dementia in Sheffield. Public information and interest in donations |
Year(s) Of Engagement Activity | 2014 |
Description | Short film about dementia research in Sheffield |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Claire Garwood received funding from the Engaged Curriculum to produce a short film about the broad range of dementia research at the University of Sheffield. |
Year(s) Of Engagement Activity | 2015 |
Description | Talk to Ignite Academy Event |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Talk given by member of our group "Astrocytes:Guardians of the Brain" Better public information |
Year(s) Of Engagement Activity | 2014 |
Description | Visit by Alzheimer's Society network volunteers |
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 | Supporters |
Results and Impact | Stephen Wharton Organised visit by Alzheimer's Society network volunteers. Nov 10 2015. 3 visitors - meet the group, 2 talks and lab tour. |
Year(s) Of Engagement Activity | 2015 |
Description | Visit by lay monitors |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Visit by lay monitors to discuss our work on dementia |
Year(s) Of Engagement Activity | 2019 |
Description | Visit to local primary school |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Visit to local primary school by team members, Key stages 1-2. Talk and workshop focused on the brain. |
Year(s) Of Engagement Activity | 2019 |
Description | Workshops in primary schools |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Claire Garwood, Laura Ratcliffe and Irina Villasenor. Sheffield Festival of Science and Engineering. 3 Half day workshops in local primary schools "Your Amazing Brain". |
Year(s) Of Engagement Activity | 2015 |