Crosstalk between extravascular coagulation, chemokine networks and immunity in fibroproliferative lung disease

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

When the lungs are damaged by pollution, smoke, trauma or infection, the coagulation cascade system of blood clotting proteins (coagulation factors), is activated in order to temporarily plug damaged blood vessels. Aside from their roles in clotting, many of these coagulation factors can also directly affect lung repair mechanisms. In lung disease, this process can snowball - unwarranted activation of the coagulation cascade has been implicated in the excessive scarring known as fibrosis, which leads to the eventual loss of normal lung function in adults, children and premature infants. There are currently no effective therapies, so the insidious progression of fibrosis often results in death of affected individuals. New therapies are therefore urgently required. Encouragingly, the results of a recent clinical trial support the notion that anti-coagulant drugs may be beneficial. Our work has identified a particular coagulation factor which, unusually, is made within the lung itself. This project will begin to identify the mechanisms by which this and other coagulation factors can lead to lung inflammation and scarring, using an experimental model of fibrosis, cultured cells and patient biopsy material. This information will help in the development of more specific and useful therapies for this devastating and fatal disease.

Technical Summary

Introduction: Uncontrolled activation of the coagulation cascade contributes to the pathophysiology of several respiratory conditions, including pulmonary fibrosis. Current dogma assumes that coagulation zymogens are derived from the circulation and locally-activated in response to tissue injury. However, my recent data show for the first time that coagulation factor X (FX) gene expression is significantly upregulated in pulmonary fibrosis and that the bronchial/alveolar epithelium represents a prominent cellular source of FX - the activated form of which (FXa) exerts potent pro-inflammatory/pro-fibrotic effects. These findings herald a paradigm shift in our understanding of the tissue origin of excessive procoagulant signaling in lung disease, and are consistent with the existence of an inducible extravascular lung coagulation system. Our work has also highlighted the involvement of proteinase-activated receptor 1 (PAR1) as the major signaling receptor for coagulation proteinases in the injured lung. Hypothesis: Extravascular pro-coagulant activity, signaling via PAR1, influences innate immune mechanisms and chemokine production to drive the development of lung inflammation and fibrosis. Aims: My aims are to determine: a) the relative contribution of locally-produced and activated FX to experimental lung inflammation and fibrosis; b) the mechanisms mediating increased FX gene expression; c) how FXa (via its receptor, PAR1) contributes to the establishment of chemokine networks involved in recruitment of leukocytes and circulating mesenchymal progenitor cells to the injured lung; and d) the significance of extravascular pro-coagulant activity for monocyte/macrophage activation and formation of secondary lymphoid tissue. Methods: These studies will employ an integrated approach involving a well-established animal model of inflammation/fibrosis, in vitro biology and patient material. FX production/activity in vivo will be manipulated using shRNA or a specific FXa inhibitor. Immunohistochemistry, ELISA, flow cytometry and real-time RT-PCR will be used to elucidate effects on inflammation/fibrosis and chemokine networks. In vitro cell biology, including both mono- and co-culture experiments, will be used to investigate FX gene regulation, and determine cross-talk between epithelium and fibroblasts or macrophages. Patient biopsy material and bronchoalveolar lavage fluid will be used to underpin this basic science programme and ensure findings are of human disease relevance. Outcomes: Besides expanding our knowledge of the fundamental crosstalk between the coagulation cascade, inflammation and immunity, this work will provide novel insights into the pathophysiological mechanisms underlying lung inflammation and fibrosis. Interfering with FX production or signaling may represent an extremely attractive target for therapeutic intervention in lung injury and fibrosis, and potentially other lung diseases associated with excessive pro-coagulant activity.

Publications

10 25 50

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Chambers RC (2012) Coagulation cascade proteinases in lung injury and fibrosis. in Proceedings of the American Thoracic Society

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Chambers RC (2015) Mechanisms of alveolar epithelial injury, repair, and fibrosis. in Annals of the American Thoracic Society

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Datta A (2011) Novel therapeutic approaches for pulmonary fibrosis Pulmonary fibrosis in British Journal of Pharmacology

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Datta A (2013) Evidence for a functional thymic stromal lymphopoietin signaling axis in fibrotic lung disease. in Journal of immunology (Baltimore, Md. : 1950)

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Jayasinghe SN (2015) Platform Technologies for Directly Reconstructing 3D Living Biomaterials. in Advanced materials (Deerfield Beach, Fla.)

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Jayasinghe SN (2011) Bio-electrosprayed living composite matrix implanted into mouse models. in Macromolecular bioscience

 
Description Academy of Medical Sciences Task Force, for 'Increasing engagement with, and providing support to earlier career researchers'
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Epithelial Cells in Idiopathic Pulmonary Fibrosis
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description BBSRC Industrial CASE Studentship
Amount £125,281 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2010 
End 09/2014
 
Description Fast Track Grant Application
Amount £37,900 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2011 
End 01/2012
 
Description PhD Studentship
Amount £61,000 (GBP)
Organisation University of Exeter 
Department Medical School
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 09/2017
 
Description Research grant
Amount £4,098 (GBP)
Organisation Northcott Devon Medical Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2014 
End 04/2015
 
Title Cell-bearing matrices 
Description Bio-engineering approaches have been used to generate complex cell-scaffold composites, combining mammalian cells with natural or artificial extracellular matrix. These cell-bearing matrices are of use for studying cell-matrix and cell-cell interactions, and also have clear implications for regenerative medicine approaches. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Provided To Others? No  
Impact The proof-of-concept work has been published (PMID: 21755598), and a grant has been submitted to progress the work further. A follow-up study has recently been published (PMID: 26508202) . 
URL http://europepmc.org/abstract/MED/21755598
 
Title Micro-CT scanning of experimental lung fibrosis 
Description Use of micro-CT scanning technology to generate high resolution scans of experimentally-induced murine lung fibrosis, combined with an analytical approach using pattern recognition software, to provide a highly sensitive novel endpoint measure of fibrosis. 
Type Of Material Technology assay or reagent 
Year Produced 2012 
Provided To Others? Yes  
Impact This approach directly addresses the 3Rs, since it refines the use of our existing animal model of lung fibrosis, and reduces the number of animals required. This work has been published (PMID: 23520313) 
 
Title Standardised isolation of primary human lung epithelium 
Description I have contributed expert knowledge to an international consortium that aims to standardise the protocols for isolation and characterisation of primary human lung epithelial cells. 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact A consensus statement regarding the appropriate use of epithelial cells in IPF research was delivered to the International Colloquium on Lung Fibrosis in November 2010. 
 
Title Three-dimensional in vitro model for pre-clinical drug evaluation in lung fibrosis 
Description We developed a three-dimensional in vitro culture system, aimed at better recapitulating a feature (fibrotic foci) of human disease (lung fibrosis) which is not seen in animal models. This in vitro system was then characterized for its potential as a medium-throughput screening tool for pre-clinical drug evaluation. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Provided To Others? No  
Impact A publication is due for submission shortly. 
 
Title MicroCT analysis of murine lungs 
Description Development of a novel endpoint measure (microCT imaging) for quantification of lung fibrosis in murine models of lung disease, in an effort to improve pre-clinical drug testing and reduce animal use. 
Type Of Material Data analysis technique 
Year Produced 2013 
Provided To Others? Yes  
Impact In my own research, use of this approach has reduced animal use. The data analysis approach is now being used by a number of research groups, and publications are slowly emerging. 
URL http://erj.ersjournals.com/content/42/6/1633.long
 
Description Cell therapy for lung fibrosis (HSC-KGF study) 
Organisation University College London
Department Centre for Respiratory Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual and technical input
Collaborator Contribution Collaboration on the use of lentivirus has provided technical experience for their use in Aim 1 of this MRC fellowship
Impact 19956603
Start Year 2007
 
Description Consensus on Epithelial Cells in Idiopathic Pulmonary Fibrosis 
Organisation Imperial College London
Department National Heart & Lung Institute (NHLI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of expert knowledge, and eventually access to human tissue samples
Collaborator Contribution Access to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertise
Impact A consensus statement on the appropriate use of epithelial cells in Idiopathic Pulmonary Fibrosis research was presented at the International Colloquium on Lung Fibrosis in November 2010. The eventual aim of all the participants is to set up a UK-wide consortium for the sharing of knowledge and access to human lung samples.
Start Year 2010
 
Description Consensus on Epithelial Cells in Idiopathic Pulmonary Fibrosis 
Organisation Newcastle University
Department Institute of Cellular Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of expert knowledge, and eventually access to human tissue samples
Collaborator Contribution Access to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertise
Impact A consensus statement on the appropriate use of epithelial cells in Idiopathic Pulmonary Fibrosis research was presented at the International Colloquium on Lung Fibrosis in November 2010. The eventual aim of all the participants is to set up a UK-wide consortium for the sharing of knowledge and access to human lung samples.
Start Year 2010
 
Description Consensus on Epithelial Cells in Idiopathic Pulmonary Fibrosis 
Organisation University of Bristol
Department School of Social and Community Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of expert knowledge, and eventually access to human tissue samples
Collaborator Contribution Access to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertise
Impact A consensus statement on the appropriate use of epithelial cells in Idiopathic Pulmonary Fibrosis research was presented at the International Colloquium on Lung Fibrosis in November 2010. The eventual aim of all the participants is to set up a UK-wide consortium for the sharing of knowledge and access to human lung samples.
Start Year 2010
 
Description Consensus on Epithelial Cells in Idiopathic Pulmonary Fibrosis 
Organisation University of California, San Francisco
Department School of Medicine (UCSF)
Country United States 
Sector Academic/University 
PI Contribution Sharing of expert knowledge, and eventually access to human tissue samples
Collaborator Contribution Access to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertise
Impact A consensus statement on the appropriate use of epithelial cells in Idiopathic Pulmonary Fibrosis research was presented at the International Colloquium on Lung Fibrosis in November 2010. The eventual aim of all the participants is to set up a UK-wide consortium for the sharing of knowledge and access to human lung samples.
Start Year 2010
 
Description Consensus on Epithelial Cells in Idiopathic Pulmonary Fibrosis 
Organisation University of Edinburgh
Department MRC Centre for Inflammation Research
Country United Kingdom 
Sector Public 
PI Contribution Sharing of expert knowledge, and eventually access to human tissue samples
Collaborator Contribution Access to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertise
Impact A consensus statement on the appropriate use of epithelial cells in Idiopathic Pulmonary Fibrosis research was presented at the International Colloquium on Lung Fibrosis in November 2010. The eventual aim of all the participants is to set up a UK-wide consortium for the sharing of knowledge and access to human lung samples.
Start Year 2010
 
Description Consensus on Epithelial Cells in Idiopathic Pulmonary Fibrosis 
Organisation University of Leicester
Department Department of Infection, Immunity and Inflammation
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of expert knowledge, and eventually access to human tissue samples
Collaborator Contribution Access to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertise
Impact A consensus statement on the appropriate use of epithelial cells in Idiopathic Pulmonary Fibrosis research was presented at the International Colloquium on Lung Fibrosis in November 2010. The eventual aim of all the participants is to set up a UK-wide consortium for the sharing of knowledge and access to human lung samples.
Start Year 2010
 
Description Consensus on Epithelial Cells in Idiopathic Pulmonary Fibrosis 
Organisation University of Nottingham
Department School of Biomedical Sciences Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of expert knowledge, and eventually access to human tissue samples
Collaborator Contribution Access to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertise
Impact A consensus statement on the appropriate use of epithelial cells in Idiopathic Pulmonary Fibrosis research was presented at the International Colloquium on Lung Fibrosis in November 2010. The eventual aim of all the participants is to set up a UK-wide consortium for the sharing of knowledge and access to human lung samples.
Start Year 2010
 
Description Consensus on Epithelial Cells in Idiopathic Pulmonary Fibrosis 
Organisation University of Sheffield
Department Department of Infection, Immunity and Cardiovascular Disease
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of expert knowledge, and eventually access to human tissue samples
Collaborator Contribution Access to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertise
Impact A consensus statement on the appropriate use of epithelial cells in Idiopathic Pulmonary Fibrosis research was presented at the International Colloquium on Lung Fibrosis in November 2010. The eventual aim of all the participants is to set up a UK-wide consortium for the sharing of knowledge and access to human lung samples.
Start Year 2010
 
Description Consensus on Epithelial Cells in Idiopathic Pulmonary Fibrosis 
Organisation University of Southern California
Department Keck School of Medicine
Country Unknown 
Sector Academic/University 
PI Contribution Sharing of expert knowledge, and eventually access to human tissue samples
Collaborator Contribution Access to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertiseAccess to human tissue samples and/or sharing of expertise
Impact A consensus statement on the appropriate use of epithelial cells in Idiopathic Pulmonary Fibrosis research was presented at the International Colloquium on Lung Fibrosis in November 2010. The eventual aim of all the participants is to set up a UK-wide consortium for the sharing of knowledge and access to human lung samples.
Start Year 2010
 
Description Gammaherpesvirus infection of lung epithelium 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are investigating the role of gammaherpesvirus infection in the exacerbation of underlying fibrotic lung disease. This work also involves in vitro studies of mechanisms of viral infection in lung epithelium.
Collaborator Contribution Professor Paul Kellam and his team were able to provide use with live Kaposi's Sarcoma Herpesvirus for use in our in vitro studies, plus intellectual input regarding data interpretation.
Impact A manuscript describing this work is currently under preparation for publication.
Start Year 2012
 
Description Generation of cell-scaffold composites using bio-engineering 
Organisation University College London
Department Mechanical Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution I provided the cellular material and the biological expertise for characterising the cellular phenotype after creation of the cell-scaffold composites.
Collaborator Contribution One aim of my CDA was to investigate cell-cell interactions using a simple co-culture system. This collaboration enabled the use of cutting-edge bioengineering approaches to specifically seed cells within a three-dimensional protein scaffold. Refinement of this process should expedite my cell co-culture research, and could also have relevance for regenerative medicine.
Impact This work has resulted in two publications (PMID: 21755598 and 26508202). This collaboration involves the life sciences, medicine and engineering.
Start Year 2010
 
Description Goblet cell metaplasia study 
Organisation University of Cagliari
Country Italy 
Sector Academic/University 
PI Contribution Intellectual and technical input, plus provision of research facilities.
Impact 19307611
Start Year 2007
 
Description Goblet cell metaplasia study 
Organisation University of Siena
Country Italy 
Sector Academic/University 
PI Contribution Intellectual and technical input, plus provision of research facilities.
Impact 19307611
Start Year 2007
 
Description Micro-CT scanning of experimental lung fibrosis 
Organisation GlaxoSmithKline (GSK)
Department Fibrosis DPU
Country United Kingdom 
Sector Private 
PI Contribution This work has defined a novel endpoint for analysis of experimental murine lung fibrosis - which is the principal animal model utlised in my CDA. The work should allow more sensitive and reproducible analysis of this animal model, using cutting-edge imaging technology, while reducing the number of animals required.
Collaborator Contribution Provision of access to cutting edge micro-CT scanning technology and analytical software.
Impact This work is now published. PMID: 23520313. Multi-disciplinary - medical imaging, pathology and experimental medicine
Start Year 2010
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation Durham University
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation Royal Marsden NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation St George's University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Tissue Remodeling and Fibrosis Research Consortium 
Organisation University of York
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-investigator in the Tissue Remodeling and Fibrosis Research Consortium, which is part of the MRC Mouse Network to link in with the International Mouse Phenotyping Consortium. The aims of this consortium are to define the critical regulatory networks underlying the pathogenesis of organ/tissue-based fibrosis and tissue remodelling processes, delineate the cellular and molecular links between tissue injury, subsequent remodeling and the development of fibrosis, and to identify organ-selective and common anti-fibrotic targets. By combining our expertise, we will utilize novel gene knockout mice to discover and develop novel therapies for the treatment of fibrotic diseases, translating our findings into the clinical arena to enhance patient management and treatment.
Collaborator Contribution As part of this research consortium, we will have access to a variety of knockout mice as part of the MRC Mouse Network.
Impact Our original Expression of Interest was successful. The members of the consortium organised a one-day meeting to discuss each other's research and how the consortium will move forward once the various knockout mice become available. A follow-up meeting is in the planning stages.
Start Year 2011
 
Description Charity launch, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact On January 19th 2011, the "Breathing Matters" charitable fund was officially launched. The event was attended by over 120 patients (and family members) who were invited to hear a series of presentations about the Centre for Respiratory Research. I presented research from my CDA in the form of a poster, which required explanation to the lay audience. Subsequently, I attended various Breathing Matters events, aimed at engaging with patients and the public.

Feedback from the patient participants showed that they found it extremely informative, and were grateful for the opportunity to meet with the research and clinical staff in our centre, to discuss what research is being performed.
Year(s) Of Engagement Activity 2011,2012,2013
 
Description Division of Medicine Careers Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Around 30 post-graduate students attended the Division of Medicine Careers Event at UCL, to give them information about the potential careers open to them at the end of their studies. I was asked to talk about a career in Academia.

Unknown.
Year(s) Of Engagement Activity 2011,2012,2013
 
Description In2ScienceUK 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact Two A-level students from underpriveleged backgrounds were hosted in our centre for a two-week placement.

Rebecca McKelvey, founder of In2ScienceUK, won the Teach First "Higher Education Access Programme for Schools" Award in 2011, highlighting the impact of this programme.
Year(s) Of Engagement Activity 2012,2013
 
Description Patient engagement through Breathing Matters charity 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Supporters
Results and Impact This was a fundraising and patient engagement activity, which resulted in additional donations, and positive feedback from patients and their families who had the opportunity to meet the researchers.

Additional charitable donations
Year(s) Of Engagement Activity 2013
URL http://www.breathingmatters.co.uk