The Role of Cyclin-Dependent Kinase-9 Inhibition in Promoting the Resolution of Chronic Inflammation

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Inflammation Research

Abstract

Disordered inflammation is responsible for most of the diseases afflicting western society, including hardening of the arteries (causing heart attacks, stroke and peripheral vascular disease), lung diseases (including chronic bronchitis and asthma), crippling rheumatoid and osteoarthritis, and the commonest forms of liver and kidney disease necessitating transplantation. Despite the huge burden of illness, loss of work and ultimately death, there is yet no effective drug therapy for most of these conditions.
Previous approaches to drug development have been targeted at interfering at single points within a hugely complex process that involves thousands of mediators, many of which duplicate and triplicate each other's effects. With MRC support over the last twenty years we have been taking an entirely different approach. While some forms of inflammation (pneumonia and acute gout, for example) cause dramatic inflammatory diseases they have the capacity to resolve completely with no residual damage to surrounding tissues. Starting from this observation we have been studying how these conditions resolve in order to generate new therapies for the vast majority of inflammatory diseases that fail to resolve 'in the fashion nature intended' and therefore result in chronic inflammation and ill-health.
Our major early discovery was that certain damaging white blood cells need to undergo a form of 'silent suicide' and be quietly removed by local scavenger cells in order for inflammation to resolve effectively. We spent several years working out the detailed mechanisms of this process in order to attempt to harness them for therapeutic gain. In the 'test-tube' we found many ways of 'driving' these suicide and clearing-up processes, but whenever we tried to reproduce the results in mouse models of human disease the beneficial effects were counteracted by the presence of powerful cell-survival factors in live tissues.
The 'breakthrough' came at the beginning of our current MRC programme grant when we showed that agents called cyclin-dependent kinase (CDK) inhibitor drugs not only drove the cell suicide process in the presence of survival factors in the test tube, but greatly accelerated the rate of resolution in mouse lung models of human inflammatory/scarring diseases. This effectively 'squared the circle' on twenty years of preparatory work.
In the past four years we have homed in on the specific molecules involved in this exciting discovery in order to build a strong scientific foundation for better targeted, less toxic new drugs. We have now clearly identified the molecule CDK9 for close attention in our new research programme, and shown that CDK inhibitor drugs not only drive cell suicide but also cause the 'scavenger' cells to release anti-inflammatory agents, thus adding to the drug's potential therapeutic benefit. Furthermore, we have shown that CDK inhibitor drugs cause resolution of inflammation not only in the lung but also in a mouse model of the inflammatory process responsible for hardening of the arteries and its consequences. Thus in our new programme of research we will extend our studies to clinically relevant models of vascular, liver and kidney disease, in the likelihood that our work will have widespread relevance for the development of new treatments for inflammatory/scarring diseases of all organs.

Technical Summary

By demonstrating that CDK inhibitor drugs (CDKi) promote the resolution of lung inflammation through a process which involves 'driving' neutrophil apoptosis, we achieved a key aim of many years of MRC-funded research - showing that resolution mechanisms could be harnessed for potential therapeutic benefit. While CDKi (e.g., R-roscovitine) are beginning to be trialled in humans for various cancers, it is recognised that their specificity and toxicity profiles are not yet ideal.
We have now generated persuasive in vitro and in vivo preliminary data that CDK9 is the key target of the CDKi in a process that involves down-regulation of Mcl-1. The importance of CDK9 in vivo is supported by pilot data using transgenic zebrafish treated with morpholino antisense oligimers to specifically knockdown CDK9. We have also discovered that CDKi inhibit release of pro-inflammatory mediators from stimulated macrophages (without inhibiting efferocytosis) in what is likely to represent an additional pro-resolution benefit. We have recently shown identical pro-resolution effects of CDKi in eosinophilic inflammation, in bleomycin-induced fibrosis and, excitingly, in a mouse model of atherogenesis.
In the proposed programme we will interrogate the hypothesis that CDK9 is pivotal in maintaining chronic inflammation and their inhibition induces the resolution of chronic inflammatory/scarring diseases of the lungs and other organs. Specifically we will:

1. Test our hypothesis in zebrafish, employing a novel model of chronic atheromatous inflammation and using specific molecular knockdown approaches in
genetically modified fish.
2. Confirm the pivotal status of CDK9 in models of chronic inflammation in mice, prioritising the use of a myeloid-specific inducible CDK9 knockout mouse.
3. Establish proof-of-concept assays of pro-resolution effects of CDK9 inhibition in human inflammatory macrophages to provide a platform for drug discovery.

Planned Impact

The worldwide healthcare burden of inflammatory/scarring diseases of the lung and other organs is undeniable, as is the fact that most of these are therapeutically intractable and ultimately fatal. Our MRC-supported research showing that the processes by which inflammation resolves 'naturally' can be harnessed in a new approach to treating these diseases has already generated considerable impact. Indeed our twenty-year 'discovery pathway' is often used as an example of the cellular>animal model>human disease translation paradigm.
Our work has already resulted in considerable academic and commercial impact. It has attracted large numbers of high-quality clinical and non-clinical training fellows and continues to do so. Our proposed research programme is positioned directly at the translational interface, in terms of both clinical and commercial exploitation:
1. Our work on CDK inhibitor drugs in lung inflammation (Nature Medicine, 2006 which has been cited at least 164 times) has paved the way for a new therapeutic approach to treating inflammatory disease. We have already filed a patent application entitled 'Use of CDK inhibitor for the treatment of granulocyte mediated disorders' (No 0325931), but our proposed research on CDK9 will lead to better targeted drugs with better toxicity profiles. These will also be patented and commercially exploited.
2. The extension of our findings into a platform of potential new treatments for atheromatous vascular disease, liver and kidney fibrosis will add enormously to the impact of our current and proposed research in chronic inflammatory lung disease.
3. The research of our group has generated considerable academic impact in the inflammation and apoptosis fields, and has influenced the research of numerous groups worldwide. Our publications are widely read and highly cited. Our original observation of neutrophil apoptosis (J Clin Invest, 1989) has been cited more than 1100 times and has stimulated new research by academic groups worldwide. Since 1989 a total of >9583 academic papers have been published on 'neutrophil', 'eosinophil' or 'granulocyte' apoptosis, or programmed cell death, and most of Haslett's (>18,239) citations relate to granulocyte apoptosis. The metric for the applicants are as follows: AG Rossi (H-factor-36, total citations >4542) and C Haslett (H-factor-65; total citations >18,224. R. Duffin, the named senior scientist, has an H-factor of 24 with total citations of >2,933). It is predicted that these metrics will continue to grow proportionately as new publications derive from our proposed work.
4. The group continues to enjoy an excellent record of attracting high-quality scientific trainees from home and abroad and for guiding them on successful career paths. Haslett has been responsible for the supervision/sponsorship of more that twenty-five (MRC and WT) clinical training fellows at different levels of seniority, many of whom now run their own research groups in branches of this field. Two new Training Fellows are now associated with the current programme. The UoE CMVM has a strong history of appointing Programme Grant senior scientists to permanent positions at the end of the grant period. Previous examples include Professors Ian Dransfield and Adriano Rossi (who now heads the 'Inflammation Resolution' programme in the CIR). If the current proposal is awarded, CMVM is committed to the same plan for Dr Rodger Duffin. Thus the research programme will continue to have an important impact on scientific training and career development.

Our Research proposal therefore addresses a major area of unmet human need and fits with a number of strategic objectives in the MRC five-year Strategic Plan (2009-2014):-
- Improve human health
- Promote translation of basic research discoveries into new/improved healthcare
- Encourage commercial exploitation, for the benefit of the UK's health and economy
- Attract and train first-rate researchers.

Publications

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Alessandri AL (2013) Resolution of inflammation: mechanisms and opportunity for drug development. in Pharmacology & therapeutics

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Barr LC (2013) A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation. in American journal of respiratory and critical care medicine

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Barth ND (2020) Assessment of Neutrophil Apoptosis. in Methods in molecular biology (Clifton, N.J.)

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Barth ND (2017) The "Phagocytic Synapse" and Clearance of Apoptotic Cells. in Frontiers in immunology

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Bedi P (2018) Blood Neutrophils Are Reprogrammed in Bronchiectasis in American Journal of Respiratory and Critical Care Medicine

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Boyle AK (2019) Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

 
Description Dr Chengcan Yao 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Dr Chengcan Yao is a young independent researcher who has recently joined the MRC Centre for Inflammation Research. Members of my team (Dr Rodger Duffin, Calum Robb and Jennifer Felton) have a highly successful working collaboration with him and his group.
Collaborator Contribution Dr Chengcan Yao has brought expertise on important immune cells, the innate lymphoid cells, that has led to a novel avenue of research for my research team.
Impact Joint applications to research grant awarding bodies (MRC, Wellcome Trust) are in progress. Several manuscripts have are in progress two of which have been submitted for publication and one has already been published (please see below). Duffin R, O'Connor RA, Crittenden S, Forster T, Yu C, Zheng X, Smyth D, RobbCT, Rossi F, Skouras C, Tang S, Richards J, Pellicoro A, Weller RB, Breyer RM,Mole DJ, Iredale JP, Anderton SM, Narumiya S, Maizels RM, Ghazal P, Howie SE,Rossi AG, Yao C. Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis. Science. 2016 Mar 18;351(6279):1333-8. dos: 10.1126/science.aad9903. PubMed PMID: 26989254; PubMed Central PMCID: PMC4841390.
Start Year 2015
 
Description Many researchers in the MRC Centre of Inflammation University of Edinburgh 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution collaborator and mentors to many researchers - contributed to successful grant applications
Collaborator Contribution My collaborators provide significant intellectual input to my research team and effort.
Impact most of my publications feature other members of the MRC CIR UoE
Start Year 2006
 
Description 1. 13th London World Congress on Inflammation, July 8-12, 2017. Hilton London Metropole Hotel, London. GREMI (Groupe de Recherche et Etude des Médiateurs de l'Inflammation) Symposium. "Roscovitine as a new anti-inflammatory therapy promoting neutrophil apoptosis". 9th July 2017. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 13th London World Congress on Inflammation, July 8-12, 2017. Hilton London Metropole Hotel, London. GREMI (Groupe de Recherche et Etude des Médiateurs de l'Inflammation) Symposium. "Roscovitine as a new anti-inflammatory therapy promoting neutrophil apoptosis". 9th July 2017.
Year(s) Of Engagement Activity 2017
URL http://wci2017.org
 
Description 1. British Society for Immunology Inflammation Affinity Group, in conjunction with the Manchester Immunology Group. Manchester at the "Inflammation and Disease" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact British Society for Immunology Inflammation Affinity Group, in conjunction with the Manchester Immunology Group. Manchester at the "Inflammation and Disease" conference on 9th -10th of September, 2014.
Year(s) Of Engagement Activity 2014
 
Description 1. Charles Darwin House, London, UK. Flow cytometric techniques for assessing apoptosis and efferocytosis of inflammatory cells. Advances in Cytometry 2015. The Terry Hoy Lecture, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Charles Darwin House, London, UK. Flow cytometric techniques for assessing apoptosis and efferocytosis of inflammatory cells. Advances in Cytometry 2015. The Terry Hoy Lecture, 13th November 2015
Year(s) Of Engagement Activity 2015
 
Description 1. ESCCA 2016, Edinburgh, UK. "Flow cytometric techniques for assessing apoptosis and efferocytosis of inflammatory cells: strategies for enhancing the resolution of inflammation. - A 'festival of cell analysis, apoptosis and inflammation' (11-14th September, 2016). Talk on the 14th September 2016. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact ESCCA 2016, Edinburgh, UK. "Flow cytometric techniques for assessing apoptosis and efferocytosis of inflammatory cells: strategies for enhancing the resolution of inflammation. - A 'festival of cell analysis, apoptosis and inflammation' (11-14th September, 2016). Talk on the 14th September 2016.
Year(s) Of Engagement Activity 2016
 
Description 1. Edinburgh, SCRM. "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration" Wellcome Trust Site Visit, 5th August, 2016 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Edinburgh, SCRM. "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration" Wellcome Trust Site Visit, 5th August, 2016
Year(s) Of Engagement Activity 2016
 
Description 1. Pharmacology 2017, 11-13 December 2017, Queen Elizabeth II Conference Centre, London. The Japanese Pharmacological Society (JPS) and the British Pharmacological Society (BPS) Symposium. "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration". 11th December 2017. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Pharmacology 2017, 11-13 December 2017, Queen Elizabeth II Conference Centre, London. The Japanese Pharmacological Society (JPS) and the British Pharmacological Society (BPS) Symposium. "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration". 11th December 2017.
Year(s) Of Engagement Activity 2017
URL https://www.bps.ac.uk
 
Description 1. Society for Reproductive Investigation (SRI); Scientific Symposium Targeting Inflammation to Improve Reproductive Health Across the Lifecourse (John McIntyre Conference Centre, Edinburgh, 16-18th August 2017). "Enhancing the resolution of inflammation as a potential therapeutic target in the reproductive system" 17th August 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Society for Reproductive Investigation (SRI); Scientific Symposium Targeting Inflammation to Improve Reproductive Health Across the Lifecourse (John McIntyre Conference Centre, Edinburgh, 16-18th August 2017). "Enhancing the resolution of inflammation as a potential therapeutic target in the reproductive system" 17th August 2017
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/files/atoms/files/sri_programme_updated_14.8.2017.pdf
 
Description 1. University of Adriano Rossi invited to give plenary talk. Birmingham, Symposium of Mechanism of Inflammation (Wellcome Trust Mechanisms of Inflammatory Diseases PhD Programme). Plenary presentation "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration" 5th Oct 2018 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact University of Birmingham, Symposium of Mechanism of Inflammation (Wellcome Trust Mechanisms of Inflammatory Diseases PhD Programme). Plenary presentation "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration" 5th Oct 2018


AGR Invited to join the Wellcome Trust DTP on Inflammatory Disease Advisory Board for the programme.
Year(s) Of Engagement Activity 2018
 
Description 11th World Congress on Inflammation, Natal RN, Brazil, September, 21-25, 2013. Invited speaker "Driving inflammatory cells apoptosis to resolve inflammation". 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 11th World Congress on Inflammation, Natal RN, Brazil, September, 21-25, 2013. Invited speaker "Driving inflammatory cells apoptosis to resolve inflammation". Scheduled 24th Sept, 2013
Year(s) Of Engagement Activity 2013
 
Description 16th ANCA and Vasculitis Meeting, Paris, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 16th ANCA and Vasculitis Meeting, Paris, 14-17th April 2013. Plenary lecture entitled "Apoptosis, apoptotic cell clearance and resolution of inflammation"
Year(s) Of Engagement Activity 2013
URL http://www.sciencedirect.com/science/journal/07554982/42/4
 
Description 52nd Brazilian Congress of Pharmacology and Experimental Therapeutics - SBFTE 2020. Keynote speaker talk entitled "Regulation of apoptotic cell clearance during the resolution of inflammation". 12th November 2020 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 52nd Brazilian Congress of Pharmacology and Experimental Therapeutics - SBFTE 2020. Keynote speaker talk entitled "Regulation of apoptotic cell clearance during the resolution of inflammation". 12th November 2020
Year(s) Of Engagement Activity 2020
 
Description 55th International Conference on the Bioscience of Lipids. Aberdeen, Scotland. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 55th International Conference on the Bioscience of Lipids. Aberdeen, Scotland. June 23-27th 2014. Invited speaker- plenary session.
Year(s) Of Engagement Activity 2014
URL http://conference.researchbib.com/view/event/36404
 
Description 7th Munster Immunology meeting Keynote speaker 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 7th Munster Immunology meeting. Theme: Growing diversity in the Immune System. Keynote speaker talk entitled "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration" 29th November 2019.
Year(s) Of Engagement Activity 2019
 
Description AGR invited speaker. St. George's University of London Seminar. Invited seminar entitled "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration" Seminar on the 26th October 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited speaker
Year(s) Of Engagement Activity 2018
 
Description AGR keynote speaker. Banff, Alberta, Canada. Invited presentation "Inflammation resolution: An evolutionary conserved process". 11th Biennial Banff Inflammation Workshop (24-27th January 2019). Talk on 26th January 2019. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Aimed at researchers and postgraduate - scientific collaborations and research discussed.
Year(s) Of Engagement Activity 2019
 
Description Adriano Rossi - Invited speaker - Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA. Presentation for the Cleveland IDEAS symposium on September 16-18, 2018. Invited presentation "Resolving Inflammation to Enhance Tissue Repair in the Lung: Implications for the Gut. Talk on the 18th Sept 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker aimed at researchers to generate new ideas and approaches in the field of gastoenetrology
Year(s) Of Engagement Activity 2018
 
Description Adriano Rossi - invited speaker. Heriot-Watt University, NC3Rs Symposium. Presentation entitled "Cellular and mechanistic processes linking inflammation and tissue repair: use of zebrafish larvae" Talk on the 14th May 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact NC3R grant holders, supporters and postgraduate students - current research discussed.
Year(s) Of Engagement Activity 2018
 
Description Adriano Rossi - invited speaker. University of Edinburgh. "Show and Tell" Meeting on Innate Immunity of the Brain and Body. Presentation entitled "Targeting myeloid cells to promote resolution of inflammation and tissue repair" on the 23rd April 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact University of Edinburgh. "Show and Tell" Meeting on Innate Immunity of the Brain and Body. Presentation entitled "Targeting myeloid cells to promote resolution of inflammation and tissue repair" on the 23rd April 2018

To foster new collaborations between inflammation and neuroscientists
Year(s) Of Engagement Activity 2018
 
Description Adriano Rossi invited speaker. France, Becason, Conference entitled '1st resolution Days: the resolution of inflammation, opportunities for innovative therapeutics' on April 4-6th 2018. Presentation entitled "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration" on the 6th April 2018. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Attended by key scientists and their teams including post-graduate students
Year(s) Of Engagement Activity 2018
 
Description Adriano Rossi talk presentation. NC3rs London symposium. Talk entitled "Cellular and mechanistic processes linking inflammation and tissue repair: use of zebrafish larvae on the 23rd March 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Postgraduate students and NC3Rs grant holders and members of the NC3Rs attended
Year(s) Of Engagement Activity 2018
 
Description Banff, Canada 2017. "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration". 10th Biennial Banff Inflammation Workshop (26-29th January 2017). Talk on 27th January 2017. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Banff, Canada 2017. "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration". 10th Biennial Banff Inflammation Workshop (26-29th January 2017). Talk on 27th January 2017.
Year(s) Of Engagement Activity 2017
URL https://www.ucalgary.ca/biw2017/
 
Description British Association Lung Research (BALR) Summer Meeting. Discovery to Recovery: still lost in translation? Queens University, Belfast. 30th August-1st September 2017. Zebrafish and mouse models of 'lung' inflammation - pros and cons! 31st August 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact British Association Lung Research (BALR) Summer Meeting. Discovery to Recovery: still lost in translation? Queens University, Belfast. 30th August-1st September 2017. Zebrafish and mouse models of 'lung' inflammation - pros and cons! 31st August 2017
Year(s) Of Engagement Activity 2017
URL https://www.balr.co.uk
 
Description Cardiff University, Cardiff School of Dentistry. "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration". 3rd March 2017. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Cardiff University, Cardiff School of Dentistry. "Therapeutic strategies to enhance the resolution of inflammation to promote tissue repair and regeneration". 3rd March 2017.
Year(s) Of Engagement Activity 2017
 
Description Convegno su Nuove Prospettive in Chimica Farmaceutica (NPCF7), Savigliano, Italy, 29-31 May 2013. Keynote Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Convegno su Nuove Prospettive in Chimica Farmaceutica (NPCF7), Savigliano, Italy, 29-31 May 2013. Keynote Lecture "An introduction to the initiation, propagation and resolution of inflammation: Targeting the resolution of inflammation by pharmacological intervention" 20 May, 2013
Year(s) Of Engagement Activity 2013
 
Description Cyto 2017 Boston, 32nd Congress of the International Society for Advancement of Cytometry, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Cyto 2017 Boston, 32nd Congress of the International Society for Advancement of Cytometry, Hynes Convention Center, Boston, Massachusetts, USA. ACEA Symposium. "Flow Cytometric Assessment, Quantification and Regulation of Human Neutrophil Extracellular Traps (NETs)". 12th June 2017
Year(s) Of Engagement Activity 2017
URL http://cytoconference.org/2017/Home.aspx
 
Description FlowUK Edinburgh. Adriano Rossi - Organizer and Speaker in the Workshop on "Stem Cells in Focus". Presentation entitled "Stem cells in focus: an introduction" on the 19th July 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact FlowUK Edinburgh. Organizer and Speaker in the Workshop on "Stem Cells in Focus". Presentation entitled "Stem cells in focus: an introduction" on the 19th July 2018

National conference aimed at researchers and the flow cytometry community.
Year(s) Of Engagement Activity 2018
 
Description Foz do Iguazu, Brazil. "Pharmacological strategies to enhance the resolution of inflammation" 48th Brazilian Congress of Pharmacology and Experimental Therapeutics and the 21st Latin American Congress of Pharmacology (47th October 2016). Talk on the 6th October 2016. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Foz do Iguazu, Brazil. "Pharmacological strategies to enhance the resolution of inflammation" 48th Brazilian Congress of Pharmacology and Experimental Therapeutics and the 21st Latin American Congress of Pharmacology (47th October 2016). Talk on the 6th October 2016.
Year(s) Of Engagement Activity 2016
URL http://www.socesfar.es/index.php/our-services-4/our-services-5/our-services-9/250-48-brazilian-congr...
 
Description Goethe University, Translation Research Innovation- Pharma, Frankfurt. "Resolution of Inflammation" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Goethe University, Translation Research Innovation- Pharma, Frankfurt. "Resolution of Inflammation" 6th July 2015
Year(s) Of Engagement Activity 2015
 
Description Heriot-Watt University, School of Life Science, Edinburgh, UK. "Strategies for enhancing the resolution of inflammation" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Heriot-Watt University, School of Life Science, Edinburgh, UK. "Strategies for enhancing the resolution of inflammation" 25th November, 2015
Year(s) Of Engagement Activity 2015
 
Description IUPHAR, Edinburgh, 2016. "Pharmacological strategies to enhance the resolution of inflammation. NC-IUPHAR and BPS Focused Meeting on the Guide to Immunopharmacology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact IUPHAR, Edinburgh, 2016. "Pharmacological strategies to enhance the resolution of inflammation. NC-IUPHAR and BPS Focused Meeting on the Guide to Immunopharmacology (9-10th April, 2016). Talk on the 9th April 2016.
Year(s) Of Engagement Activity 2016
 
Description Invited speaker at Summer School, Leiden, Netherlands 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Summer School, Leiden, Netherlands. 8-12 July 2019. Immune modulation in human and animal infection; impact on health, disease and therapy. Lecture on the 10th July 2019 entitled "Host-directed therapies and check point modulation in infectious disease".
Year(s) Of Engagement Activity 2019
 
Description MRC Centre for Inflammation away day, Appleton Tower, Edinburgh. "Therapeutic Strategies to Enhance the Resolution of Inflammation to Promote Tissue Repair and Regeneration". 29th June 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 Postgraduate students
Results and Impact MRC Centre for Inflammation away day, Appleton Tower, Edinburgh. "Therapeutic Strategies to Enhance the Resolution of Inflammation to Promote Tissue Repair and Regeneration". 29th June 2017
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/inflammation-research
 
Description Magdalena Oremek presented (Adriano Rossi attended) - 31st May 2018, oral presentation: European Society for Clinical Investigation (ESCI) Phagocyte workshop. Presentation title: "Cellular and mechanistic processes linking inflammation and tissue repair" Magdalena was awarded travel grant 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact European Scientific Meeting
Year(s) Of Engagement Activity 2018
 
Description Nature Reviews Immunology. Resolving Inflammation conference 
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 Nature Reviews Immunology. Resolving Inflammation: Mechanisms and Drug Discovery, Keble College, Oxford, UK. April 1-3, 2012. Talk entitled "Targeting inflammatory cell apoptosis to resolve inflammation". Invited speaker in plenary session.

URL- http://www.nature.com/content/conferences/23393-02.html?WT.i_dcsvid=%%LIST_ID%%-%%RECIPIENT_ID%%&WT.ec_id=MARKETING
Year(s) Of Engagement Activity 2012
 
Description Novartis Institutes for BioMedical Research, Autoimmunity, Transplantation & Inflammation Disease Area, Basel, Switzerland. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Novartis Institutes for BioMedical Research, Autoimmunity, Transplantation & Inflammation Disease Area, Basel, Switzerland. "Apoptosis, Efferocytosis and the Resolution of Inflammation". 6th May 2014.
Year(s) Of Engagement Activity 2014
 
Description Our papers are frequently highlighted in the press 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A list of manuscript published by my research team and collaborators that have been highlighted in the University websites and twitter accounts and the general press are listed below (some examples of media outlets have been given).

Dorward DA, Felton JM, Robb CT, Craven T, Kipari T, Walsh TS, Haslett C, Kefala K, Rossi AG, Lucas CD. The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome. Thorax. 2017 Feb;72(2):182-185. doi: 10.1136/thoraxjnl-2016-209229. PubMed PMID: 27965411; PubMed Central PMCID: PMC5284332.

http://science.newsln.jp/news/2016110315440074.html
https://scifeeds.com/news/immune-cell-insight-offers-hope-for-tackling-deadly-lung-condition/

Hoodless LJ, Lucas CD, Duffin R, Denvir MA, Haslett C, Tucker CS, Rossi AG. Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo. Sci Rep. 2016 Nov 11;5:36980. dei: 10.1038/srep36980. PubMed PMID: 27833165; PubMed Central PMCID: PMC5105078.

http://www.eveningtimes.co.uk/news/14987467.Zebrafish_used_by_Scots_scientists_to_help_study_new_therapies_for_lung_disorders/
http://www.heraldscotland.com/news/14987467.Zebrafish_used_by_Scots_scientists_to_help_study_new_therapies_for_lung_disorders/
http://scientists.trendolizer.com/2017/01/zebrafish-used-by-scots-scientists-to-help-study-new-therapies-for-lung-disorders.html


Brook M, Tomlinson GH, Miles K, Smith RW, Rossi AG, Hiemstra PS, van 't Wout EF, Dean JL, Gray NK, Lu W, Gray M. Neutrophil-derived alpha defensives control inflammation by inhibiting macrophage mRNA translation. Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4350-5. dei: 10.1073/pnas.1601831113. PubMed PMID: 27044108; PubMed Central PMCID: PMC4843457.

http://immunitytales.com/a-molecular-brake-for-macrophage-driven-inflammation/
https://scifeeds.com/journal-article/neutrophil-derived-alpha-defensins-control-inflammation-by-inhibiting-macrophage-mrna-translation/
https://www.sciencedaily.com/releases/2016/04/160418120337.htm
http://www.ed.ac.uk/news/2016/arthritis-treatment-hope
http://www.dailymail.co.uk/health/article-3546735/Treatments-halt-pain-arthritis-set-developed-discovery-body-s-defence-switched-against-condition.html

Duffin R, O'Connor RA, Crittenden S, Forster T, Yu C, Zheng X, Smyth D, Robb CT, Rossi F, Skouras C, Tang S, Richards J, Pellicoro A, Weller RB, Breyer RM, Mole DJ, Iredale JP, Anderton SM, Narumiya S, Maizels RM, Ghazal P, Howie SE, Rossi AG, Yao C. Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis. Science. 2016 Mar 18;351(6279):1333-8. dos: 10.1126/science.aad9903. PubMed PMID: 26989254; PubMed Central PMCID: PMC4841390

https://www.eurekalert.org/pub_releases/2016-03/uoe-iss031616.php
https://www.sciencedaily.com/releases/2016/03/160317150759.htm
http://www.sciencecodex.com/immune_study_shows_how_gut_keeps_deadly_infections_at_bay-178187
http://www.ebiotrade.com/newsf/2016-3/2016317131115664.htm

Marwick JA, Dorward DA, Lucas CD, Jones KO, Sheldrake TA, Fox S, Ward C, Murray J, Brittan M, Hirani N, Duffin R, Dransfield I, Haslett C, Rossi AG. Oxygen levels determine the ability of glucocorticoids to influence neutrophil survival in inflammatory environments. J Leukoc Biol. 2013 Dec;94(6):1285-92. doi: 10.1189/jlb.0912462. PubMed PMID: 23964116; PubMed Central PMCID: PMC3855024.

https://bionews-tx.com/news/2014/03/12/chronic-bronchitis-emphysema-lung-disease-drug-ineffectiveness-explained-in-new-study/
https://stv.tv/news/east-central/266592-new-treatment-for-lung-diseases-a-step-closer-after-breakthrough/
https://m.medicalxpress.com/news/2013-12-oxygen-decrease-effectiveness-anti-inflammatory-therapies.html

Wheatley PS, Butler AR, Crane MS, Fox S, Xiao B, Rossi AG, Megson IL, Morris RE. NO-releasing zeolites and their antithrombotic properties. J Am Chem Soc. 2006 Jan 18;128(2):502-9. PubMed PMID: 16402837.

https://www.newscientist.com/article/mg18524856-700-pollution-fighter-turns-clot-buster/

Fox S, Wilkinson TS, Wheatley PS, Xiao B, Morris RE, Sutherland A, Simpson AJ, Barlow PG, Butler AR, Megson IL, Rossi AG. NO-loaded Zn(2+)-exchanged zeolite materials: a potential bifunctional anti-bacterial strategy. Acta Biomater. 2010 Apr;6(4):1515-21. toi: 10.1016/j.actbio.2009.10.038. PubMed PMID: 19861185.

http://www.ed.ac.uk/news/all-news/superbugs-231109
https://www.healthcanal.com/medical-breakthroughs/4056-new-chemical-may-play-key-role-in-hospital-superbugs-battle.html


Duffin R, Leitch AE, Sheldrake TA, Hallett JM, Meyer C, Fox S, Alessandri AL, Martin MC, Brady HJ, Teixeira MM, Dransfield I, Haslett C, Rossi AG. The CDK inhibitor, R-roscovitine, promotes eosinophil apoptosis by down-regulation of Mcl-1. FEBS Lett. 2009 Aug 6;583(15):2540-6. dos: 10.1016/j.febslet.2009.07.017. PubMed PMID: 19616548.

http://news.bbc.co.uk/1/hi/scotland/edinburgh_and_east/8403307.stm
https://www.sciencedaily.com/releases/2009/12/091209113846.htm
http://www.nursinginpractice.com/article/cancer-drug-may-work-asthma

Rossi AG, Sawatzky DA, Walker A, Ward C, Sheldrake TA, Riley NA, Caldicott A, Martinez-Losa M, Walker TR, Duffin R, Gray M, Crescenzi E, Martin MC, Brady HJ, Savill JS, Dransfield I, Haslett C. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med. 2006 Sep;12(9):1056-64.

https://www.sciencedaily.com/releases/2006/09/060903150749.htm
https://www.eurekalert.org/pub_releases/2006-09/uoe-kso090106.php


Mandal P, Chalmers JD, Graham C, Harley C, Sidhu MK, Doherty C, Govan JW, Sethi T, Davidson DJ, Rossi AG, Hill AT. Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial. Lancet Respir Med. 2014 Jun;2(6):455-63. doi: 10.1016/S2213-2600(14)70050-5. PubMed PMID: 24717640.

http://timesofindia.indiatimes.com/india/Statins-may-help-lung-disease-patients-as-well/articleshow/32674629.cms
http://www.scotsman.com/news/health/statins-may-help-those-with-lung-conditions-1-3351544
https://www.nursingtimes.net/statins-could-help-lung-patients/5069233.article?blocktitle=News-archive&contentID=700
http://www.business-standard.com/article/news-ani/cholesterol-lowering-drug-statins-could-ease-coughing-in-lung-disease-patients-114032500284_1.html
http://www.dailymail.co.uk/news/article-2587635/Doctors-fears-statins-putting-lives-risk-Professor-says-unjustified-concerns-effects-mean-drugs-not-prescribed-enough.html
http://www.heraldscotland.com/news/13152003.Statins_shown_to_help_with_chronic_coughing/
http://www.scienceworldreport.com/articles/13653/20140325/statin-cholesterol-lowering-drug-offers-relief-from-chronic-lung-disease.htm
Year(s) Of Engagement Activity 2006,2009,2010,2013,2014,2016,2017
 
Description Pharmacology, Toxicology and Therapeutics Seminar, University of Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Pharmacology, Toxicology and Therapeutics Seminar, "Killing inflammatory cells to resolve inflammation" Monday 5th November 2012, University of Edinburgh, QMRI.
Year(s) Of Engagement Activity 2012
 
Description Poster presentation by Magdalena Oremek - 24th-26th January 2019, Banff Inflammation Workshop 2019. Banff, Canada. Poster title: "Linking Inflammation and Tissue Repair using Zebrafish- the Role of the Inflammatory Cells" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact International conference- Adriano Rossi invited as key note speaker - Magdalena attended as Adriano's trainee.
Year(s) Of Engagement Activity 2019
 
Description R&D Systems Symposium "The Role of Cytokines and Signalling in Inflammation". 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact R&D Systems Symposium "The Role of Cytokines and Signalling in Inflammation". Research Centre CAESAR, Ludwig-Erhard-Allee 2, 53175 Bonn. 15th October 2013.
Year(s) Of Engagement Activity 2013
 
Description THE PETER E. DRESEL MEMORIAL LECTURE IN PHARMACOLOGY 31st March 2015, Halifax, Canada. March 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact THE PETER E. DRESEL MEMORIAL LECTURE IN PHARMACOLOGY 31st March 2015, Halifax, Canada. March. This was a prestigious yearly award in honour of Prof Dresel,
Year(s) Of Engagement Activity 2015
 
Description The Banff Inflammation Workshop, Banff, Canada. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The Banff Inflammation Workshop, Banff, Canada, (31 Jan - 3 Feb 2013). Invited speaker and plenary lecture '"Resolution solutions!". 1st Feb 2013
Year(s) Of Engagement Activity 2013
URL http://www.ucalgary.ca/irn/meeting/banff-inflammation-workshop-2013
 
Description UCB, Slough, UK. "Targeting neutrophil apoptosis to resolve lung inflammation" 3rd November 2016. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact UCB, Slough, UK. "Targeting neutrophil apoptosis to resolve lung inflammation" 3rd November 2016.
Year(s) Of Engagement Activity 2016
 
Description University of Aberdeen, Scottish Society of Cytomics SCC 2014. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact University of Aberdeen, Scottish Society of Cytomics SCC 2014. "Flow cytometric techniques for isolating and analysing leucocytes" 25-26th Sept 2014.
Year(s) Of Engagement Activity 2014
 
Description University of Edinburgh, Edinburgh-Zhejiang Joint Symposium 2014. Resolving lung inflammation, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact University of Edinburgh, Edinburgh-Zhejiang Joint Symposium 2014. Resolving lung inflammation, 3rd Sept 2014
Year(s) Of Engagement Activity 2014
 
Description University of Edinburgh. Edinburgh Infectious Disease Conference "Resolution of Inflammation: Implications for Infectious Diseases" 20th May 2015. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact University of Edinburgh. Edinburgh Infectious Disease Conference "Resolution of Inflammation: Implications for Infectious Diseases" 20th May 2015.
Year(s) Of Engagement Activity 2015
 
Description University of Edinburgh. QMRI, Public lecture "Treating injured lungs by extinguishing inflammation". Feb 11th 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact University of Edinburgh. QMRI, Public lecture "Treating injured lungs by extinguishing inflammation". Feb 11th 2015
Year(s) Of Engagement Activity 2015
 
Description University of Milan, Resolution of Inflammation in Pulmonary Diseases , 24th March 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact University of Milan, Resolution of Inflammation in Pulmonary Diseases , 24th March 2015
Year(s) Of Engagement Activity 2015
 
Description University of Sheffield, UK. Lecture in honour of Prof Moira Whyte 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact University of Sheffield, UK. Lecture in honour of Prof Moira Whyte 'Modulation Of Inflammation Resolution & Apoptosis' June 25th 2014.
Year(s) Of Engagement Activity 2014
 
Description ¬ Madelena Oremek and Adriano Rossi- 23rd March 2018, Poster session: NC3Rs day- London. Poster title: "Cellular and mechanistic processes linking inflammation and tissue repair" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact ¬ 23rd March 2018, Poster session: NC3Rs day- London. Poster title: "Cellular and mechanistic processes linking inflammation and tissue repair"
Year(s) Of Engagement Activity 2018
 
Description ¬ Magdalena Oremek and Adriano Rossi. 24th May 2018, Poster session 3Rs day University of Edinburgh- Edinburgh. Poster title: "Cellular and mechanistic processes linking inflammation and tissue repair" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact For many post-graduate and under-graduate students and University teachers
Year(s) Of Engagement Activity 2018
 
Description ¬ Talk by Adriano Rossi - Heriot-Watt University, NC3Rs Symposium. Presentation entitled "Cellular and mechanistic processes linking inflammation and tissue repair: use of zebrafish larvae" Talk on the 14th May 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Adriano Rossi gave a talk to individuals supported by grants from the NC3Rs and to members of the NC3Rs.
Year(s) Of Engagement Activity 2018