A combined genetic and small molecule approach to studying the role of the p38/MK2 stress signalling pathway in a human premature ageing syndrome
Lead Research Organisation:
Cardiff University
Department Name: Chemistry
Abstract
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Publications
Bagley M
(2011)
The contribution of biogerontology to quality ageing
in Quality in Ageing and Older Adults
Bagley MC
(2015)
Microwave-Assisted Synthesis of a MK2 Inhibitor by Suzuki-Miyaura Coupling for Study in Werner Syndrome Cells.
in Pharmaceuticals (Basel, Switzerland)
Bagley MC
(2016)
The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells.
in Organic & biomolecular chemistry
Bagley MC
(2010)
Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome.
in Pharmaceuticals (Basel, Switzerland)
Davis T
(2016)
Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts.
in Pharmaceuticals (Basel, Switzerland)
Davis T
(2011)
Investigating the role of c-Jun N-terminal kinases in the proliferation of Werner syndrome fibroblasts using diaminopyridine inhibitors.
in Chemistry Central journal
Davis T
(2013)
The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome.
in Chemistry Central journal
Joanna Latimer (Author)
(2011)
The motility of the ethical in bioscience: the case of care in anti-ageing science
Latimer J
(2020)
Biomarkers and brains: situating dementia in the laboratory and in the memory clinic.
in New genetics and society
| Description | This programme studied the premature ageing Werner syndrome (WS) that provides a powerful model system to study human ageing biology. WS is associated with rapid cell ageing, in particular acceleration of replicative senescence (the ageing of dividing cells). We previously identified a role for stress-signalling in this accelerated cell ageing involving p38 MAP kinase that also regulates the production of proinflammatory molecules such as cytokines, high levels of which are associated with diseases such as osteoporosis and type II diabetes that are more common in WS. As therapeutic targeting of p38 is problematic due to toxicity issues, we wished to further refine this stress pathway by examining the role of the downstream target MK2 in cell ageing. Using genetic modification and chemical drugs to target MK2, we asked whether MK2 inhibition prevents (or delays) cell ageing in cells from WS and non-WS individuals. We found that cell growth rates of immortal WS cells were not affected, whereas p38 inhibition increased growth rates; however, the stressed morphology of WS cells was corrected. Growth rates of mortal (primary) WS or non-WS cells were also not affected, but the stressed morphology of primary WS cells was corrected. The replicative capacity was increased for both WS and non-WS cells. Finally, MK2 inhibitors did not prevent stress-induced cell senescence. These data suggest that MK2 is not involved in stress-induced cell senescence, and add to our understanding of how cellular senescence may lead to in vivo human ageing and in the pathology of age-related inflammatory diseases. |
| Exploitation Route | It will inform future attempts to study the interaction between inflammation and ageing and future therapies targeting ageing mechanisms |
| Sectors | Healthcare,Security and Diplomacy,Transport,Other |
| URL | http://www.newdynamics.group.shef.ac.uk/stress-and-immunity.html |
| Description | They have been used by other scientists studying ageing. |
| First Year Of Impact | 2011 |
| Sector | Chemicals,Healthcare |
| Description | Identification of small molecules capable of removing ageing cells and slowing down the ageing process |
| Amount | £635,000 (GBP) |
| Funding ID | #83 |
| Organisation | Ministry of education and science of the Republic of Kazakhstan |
| Sector | Public |
| Country | Kazakhstan |
| Start | 10/2012 |
| End | 12/2014 |
| Description | A New Dynamic of Ageing: The NDA Programme and Age UK Research Showcase of the Decade |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | A one day event to showcase research findings to policy makers and stakeholders, held at the Business Design Centre London on 21st October 2013 |
| Year(s) Of Engagement Activity | |
| Description | Assessing the role of p38 MAP kinase activity in replicative senescence in fibroblasts from progeroid syndromes. |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | Poster presentation at the 61st Annual Scientific Meeting of the British Society for Research on Ageing / 14th Congress of the International Association of Biomedical Gerontology Conference: The Science of Ageing; Global Progress. |
| Year(s) Of Engagement Activity | |
| Description | Cell senescence and telomeres in the context of cancer and human ageing |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | University of Suffolk Seminar Series |
| Year(s) Of Engagement Activity | 2014 |
| Description | Intimations of (Im)mortality: how aging scientists debate the relation between the normal, the natural and the pathological |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | Keynote Presentation @ BSA Ageing Body and Society Study Group, Future of Ageing, Science Technology & the Body. British Library, London. |
| Year(s) Of Engagement Activity | |
| Description | Replication stress and ageing in Werner and ATR-Seckel syndrome fibroblasts. |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | A poster presented at the 8th European Congress of Biogerontology Conference 'Healthy Ageing and Regenerative Medicine' organised by the Ben Gurion University of the Negev Israel. |
| Year(s) Of Engagement Activity | |
| Description | Replicative senescence and human ageing processes |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | A network poster presented at 'Promoting Active and Healthy Ageing' Conference organised by Cardiff University Ageing, Science and Older People (CASciOPe) network to celebrate the United Nations International Day of Older People. |
| Year(s) Of Engagement Activity | |
| Description | Social justice and (Anti)-Ageing Science and Medicine. |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Participants in your research or patient groups |
| Results and Impact | Paper presented at a seminar Section not completed |
| Year(s) Of Engagement Activity | 2010 |
| Description | Stress Senescence and premature ageing |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | Invited Lecture |
| Year(s) Of Engagement Activity | 2014 |
| Description | Stress, senescence and premature ageing |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | Invited Lecture |
| Year(s) Of Engagement Activity | 2014 |
| Description | The role of p38MAPK in the premature ageing of skin fibroblasts |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | Invited Lecture at the British Association of Dermatologists' Conference 'Ageing Skin: Insights and Interventions' |
| Year(s) Of Engagement Activity | 2014 |
| Description | Towards a cure for adult progeria |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | Presentation on research findings concerning the role of stress signalling on premature ageing syndromes and progress towards a cure. |
| Year(s) Of Engagement Activity | 2013 |
| Description | Towards therapeutic intervention in human premature ageing syndromes |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | Presentation on current progress towards intervening in cellular ageing in premature ageing syndromes |
| Year(s) Of Engagement Activity | 2013 |
| Description | Werner syndrome and the role of stress signalling in cellular ageing |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Primary Audience | |
| Results and Impact | Presentation of research findings at the British Society for Research on Ageing annual scientific meeting Ageing Mechanisms and Mitigants. Birmingham, UK. |
| Year(s) Of Engagement Activity | 2013 |