Genetic models for connective tissue disease, scarring and fibrosis

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

When vital organs are damaged in disease this results in the development of scar tissue. When the scar is excessive or disporportionate this can itself worsen organ function, a process termed fibrosis. Fibrosis is a result of altered or abnormal healing processes and is a common factor in many common diseases. Less common disorders such as scleroderma (also called systemic sclerosis) cause fibrois in multiple organs including the skin, lungs, heart and blood vessels. We have developed, for the first time, models of fibrotic disease that can be used to study the development and consequences of fibrosis in the skin and internal organs. Through understanding these models, it is very likely that better methods for assessment and treating fibrosis will emerge.

Technical Summary

Fibrosis occurs due to excessive or inappropriate deposition of extracellular matrix in affected tissues. Systemic sclerosis is an uncommon rheumatic disease in which susceptibility to skin and visceral fibrosis leads to high mortality and morbidity. Key fibrotic mediators have been identified in SSc, including TGFbeta and CTGF. It is likely that overactivity of these mediators, or their downstream pathways, underlies the development of fibrosis in SSc and that this may also be relevant to other forms of fibrotic disease. We have developed 3 unique mouse models of fibrotic disease that recapitulate cardinal features of SSc including skin and lung fibrosis and vasculopathy. We will use these models to extend and validate molecular and imaging strategies that complement those used in human disease. The first model uses fibroblast-specific expression of a non-signalling type II TGFbeta receptor to increase constitutive TGFbeta activity in connective tissue in a ligand-dependent fashion. This leads to skin fibrosis and increased susceptibility to lung injury. The second mouse strain permits conditional fibroblast-specific high level activation of TGFbeta signalling that is ligand independent. A Cre-Lox strategy is used for fibroblast specific expression of a constitutively active mutant type I TGFbeta receptor. This strain develops marked skin and vascular fibrosis. A hallmark of both of these mouse stains is upregulation of CTGF. In the third model we have overexpressed CTGF in fibroblasts and again observe a severe skin fibrosis.
Together these complementary strains will be used to explore development of SSc associated autoantibodies and to ask whether the gene and protein expression in affected mouse organs replicates that of human SSc. A comparison of markers from these mouse models with those from scleroderma patients should increase our understanding of the diverse disease phenotypes of human scleroderma. In addition we will translate recent clinical advances in SSc assessment into these mouse strains, including novel imaging modalities, to provide a platform for future testing of targeted anti-fibrotic therapies.
 
Description Contribution to undergraduate degree in Applied Medical Sciences
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.ucl.ac.uk/prospective-students/undergraduate/degrees/ubsmedsapp05
 
Description MSc Module in Advanced Rheumatology
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description MSc/MRes Human Tissue Repair
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.ucl.ac.uk/medicine/study/postgraduate-taught-degrees/msc-mres-human-tissue-repair
 
Description Arthritis Resarch UK project grant (DA-Co-App; PI - Blandine Poulet)
Amount £190,000 (GBP)
Funding ID 20717 
Organisation Arthritis Research UK 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2015 
End 12/2018
 
Description BHF Programme grant (DA Co-Applicant; PI Prof Adrian Hobbs)
Amount £820,000 (GBP)
Funding ID RG/16/7/32357 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2016 
End 08/2021
 
Description Career Development Fellowship (DA Supervisor; Fellow Blandine Poulet)
Amount £350,000 (GBP)
Funding ID 20859 
Organisation Arthritis Research UK 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2015 
End 12/2020
 
Description PhD Studentship/UCL Grand Challenge
Amount £89,000 (GBP)
Organisation University College London (UCL) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2010 
End 09/2013
 
Description PhD Studentship/UCL/UCB Celltech Impact Award
Amount £60,000 (GBP)
Organisation University College London (UCL) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 05/2013 
End 04/2016
 
Description PhD studentship/UCL Grand Challenge
Amount £89,000 (GBP)
Organisation University College London (UCL) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 12/2011 
End 11/2014
 
Description Project Grant - EMT in Scleroderma
Amount £99,224 (GBP)
Organisation Arthritis Research UK 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2010 
End 08/2012
 
Description Project Grant - Fibrocytes in scleroderma
Amount £220,000 (GBP)
Organisation Roche 
Sector Private
Country Global
Start 03/2011 
End 02/2013
 
Description Project Grant - Remodeling in PAH
Amount £124,374 (GBP)
Organisation Arthritis Research UK 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 07/2009 
End 06/2011
 
Description Project grant
Amount £90,000 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2013 
End 07/2016
 
Description Raynaud's & Scleroderma Association (RSA) Programme Grant
Amount £410,875 (GBP)
Organisation Raynaud's & Scleroderma Association 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2012 
End 03/2014
 
Description UCL-Boehringer Ingelheim PhD Studentship
Amount £100,000 (GBP)
Organisation University College London (UCL) 
Department UCL Impact Award
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 02/2015 
End 01/2018
 
Title Hypoxic Chamber 
Description Acquisition of a hypoxic chamber for animal in vivo work used promarily as a model for human disease pulmonary arterial hypertension (PAH). 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2013 
Provided To Others? Yes  
Impact Facilitated the development of a research programe aimed at investigation molecular pathways and drug discovery in PAH 
URL http://www.coylab.com/
 
Title MRI assessment of skin fibrosis 
Description We have optimized a method for assessing murine dermal fibrosis using MRI 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact This technique has been presented at national and international conferences 
 
Title microCT assessment of murine lung fibrosis 
Description We have optimized a method for assessing murine lung fibrosis using microCT 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Data collected from microCT analysis of murine lungs forms the basis of a manuscript which is in preparation 
 
Description Analysis of anti-nuclear auto-antibodies 
Organisation Royal Free Hampstead NHS Trust
Department Royal Free Hospital
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution We provided the murine sera from genetically-modified mice for analysis of auto-antibody profiles. We have also performed statistical analysis of the data collected
Collaborator Contribution Our collaborators have provided their expertise in the identification of anti-nuclear auto-antibodies. They also performed the screening of our murine sera.
Impact We are building up a picture of the autoantibody profiles on the mouse models to comapre with the profiles in the human disease
Start Year 2009
 
Description Centre for Inflammation and Therapeutic Innovation (CiTI) QMUL 
Organisation Queen Mary College
Department Centre for Inflammation and Therapeutic Innovation
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution The new multi-disciplinary Centre for Inflammation and Therapeutic Innovation (CiTI) at Queen Mary University of London (QMUL) presents a unique opportunity for a strategic partnership aimed at exploring, endorsing, developing and testing innovative strategies for anti-inflammatory therapies with a two-way bench to bedside (and backward) approach. Citi is linked to the UCL FLARRE consortium and is develop strategic alliances in inflammation biology and tissue repair between UCLPartners and the Bio-Pharma sector
Collaborator Contribution - Development of the London Inflammation Network - Provides a framework for synergy across UCLPartners (QMUL and Barts Health NHS Trust / UCL and associated Foundation Trusts) as well as attracting external academic and industrial partners. - Contributes to exploiting therapeutic innovation alongside bioengineering and biomaterials opportunities and technical innovation within the unifying process of inflammation - Harness multi-disciplinary knowledge and know how across UCLPartners for developing innovative therapeutic approaches for patients with inflammatory and autoimmune diseases and societal benefit.
Impact Formation of the multidiscinplinary UCLPartners (UCL/QMUL) - UCB Pharma joint PhD programme
Start Year 2016
 
Description MRC Mouse Network - International Mouse Phenotyping Consortium (IMPC) 
Organisation Medical Research Council (MRC)
Department MRC Mammalian Genetics Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution The key contributions thus far are: - Development of a UK-wide consortium focusing on organ-based Tissue Repair and Fibrosis. - Co-ordination of all members to provied a comprehensive gene list within the initiative - Prioritisation of the 'first' gene set for study - Development fo objectives and targets within the consortium.
Collaborator Contribution Provision of novel conditional knock-out mice under the consortium title: Tissue Repair and Fibrosis.
Impact The main activites within this consortium are to phenotype ~100 conditional knock-out mice provied by the MRC Network in organ-based models of scarring and fibrosis. In year one, 21 prioritize genes have been submitted to the Mouse Network for initial study.
Start Year 2011
 
Description MRI analysis of murine skin 
Organisation King's College London (KCL)
Department Institute of Psychiatry (IoP)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We have provided the murine models for study and prepared the samples for scanning. We have analysed the data collected and performed histological analysis of the samples post-scanning to validate the MRI technique for analysis of skin fibrosis.
Collaborator Contribution Our collaborators have allowed access to their MRI system. They have also provided their expertise in the technique and have assisted with the data collection.
Impact This collaboration has resulted in presentations at national and international conferences. This collaboration is multi-disciplinary as it brings together the biology of skin structure, histological analysis and the physics of MRI analysis.
Start Year 2009
 
Description The role of PTEN in fibrosis 
Organisation University of Western Ontario
Department Schulich School of Medicine & Dentistry Western Ontario
Country Canada 
Sector Academic/University 
PI Contribution We have performed in vitro analysis to complement the in vivo analysis which we have performed collaboratively towards elucidating the mechanisms involved in the contribution to fibrosis made by the loss of P-I-3 kinase/AKT regulator PTEN
Collaborator Contribution Our collaborators have provided access to a further genetic murine model of fibrosis (conditional PTEN knockout). Analysis of this model has been performed collaboratively by the two groups.
Impact This collaboration has resulted in the publication of a paper: Parapuram, S.K., Xu, S., Elliott, C., Welch, I.D., Jones, H., Baron, M., Denton, C.P., Abraham, D.J., and Leask, A. (2011) Loss of PTEN expression by dermal fibroblasts causes skin fibrosis. JID 131: 1996-2003
Start Year 2010
 
Description UCL FLARRE Consortium 
Organisation UCB Pharma
Department UCB Celltech
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution We have developed a Consortiun at UCL in inflammation, tissue repair, scarring and fibrosis with the aim of promoting partnerships with Industry
Collaborator Contribution UCB celltech have co-funded a PhD studentship
Impact This partnership has just begun and aimed at indentifying common pathways to fibrosis.
Start Year 2013
 
Description UCL-YALE Collaboration 
Organisation Yale University
Department Department of Internal Medicine
Country United States of America 
Sector Academic/University 
PI Contribution Provided Lectures on the Yale Fibrosis Symposium and co-developed the frame-work for a UCL-YALE Fibrosis Consortium, and have developed a linked website.
Collaborator Contribution Hosted a Fibrosis Symposium and have co-developed the frame-work for a UCL-YALE Fibrosis Consortium
Impact The aims of the Yale-UCL Collaboration are to: • Identify areas of scientific interest between faculties working on fibrosis. • Identify common resources and complementary technologies. • Evaluate international granting opportunities. • Develop infrastructure to secure NIH, RCUK and Biomedical Charity funding • Engage in strategic alliances with the commercial sector (Pharma and Biotech)
Start Year 2013
 
Description microCT analysis of murine lung 
Organisation University College London (UCL)
Department UCL Biosciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We have provided the models for this study to examine the use of non-invasive imaging in the asessment of pulmonary fibrosis in mice. We have also performed all stages of the experimental and preparation tissue and analysis of the data.
Collaborator Contribution Our collaborators have allowed access to their microCT system. They have also provided their expertise in the technique and given training and assistance in the use of the scanner and analysis of the data collected.
Impact This collaboration has resulted in a new skill-set within our group and has also formed the basis of a manuscript which is in preparation. This collaboration is multi-disciplinary as it brings together the biology of lung structure and fibrosis and the physics of microCT scanning and the use of non-invasive imaging to assess extent of lung fibrosis.
Start Year 2011
 
Title TREATMENT AND/OR PREVENTION OF FIBROSIS 
Description The present inventors found when investigating gene expression in OcMMP fibroblasts that aldehyde dehydrogenase 1 family member A3 (ALDH1A3) is up regulated in OcMMP. Elevated expression of ALDH1A3 was then confirmed by quantitative polymerase chain reaction (qPCR) and protein levels were assessed by western blot. In view of this surprising finding, aldehyde dehydrogenase inhibitors were added to OcMMP fibroblasts, which resulted in the restoration of phenotype and function to control cell levels. These results suggest that inhibition of aldehyde dehydrogenase using aldehyde dehydrogenase inhibitors should provide an effective therapy for treating or preventing fibrosis. Accordingly, the present invention provides an aldehyde dehydrogenase inhibitor for use in the treatment or prevention of fibrosis. The invention further provides use of an aldehyde dehydrogenase inhibitor in the manufacture of a medicament for treating or preventing fibrosis. The invention further provides a method for treating or preventing fibrosis in a patient in need thereof, the method comprising adminstering to said patient an aldehyde dehydrogenase inhibitor. The invention further provides a cosmetic method for treating scarring in response to an injury in a subject, the method comprising administering an aldehyde dehydrogenase inhibitor to the subject. 
IP Reference N402793GB 
Protection Patent application published
Year Protection Granted
Licensed No
Impact Studies have implicated inhibition of aldehyde dehydrogenase as a potential therapy for treating or preventing fibrosis in mucous membrane pemphigoid (MMP), particularly ocular mucous membrane pemphigoid (OcMMP), pulmonary fibrosis, scleroderma, idiopathic pulmonary fibrosis, cystic fibrosis, cirrhosis, endomyocardial fibrosis, myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloids, arthrofibrosis, Peyronie's disease, Dupuytren's contracture and adhesive capsulitis Liver fibrosis as well as cirrhosis, atherosclerosis, cardiac fibrosis, pulmonary and peripheral vascular disease.
 
Title Vascular Remodelling 
Description A unique mechanism leading to remodelling of the blood vessels 
IP Reference 1212773.4 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact We have received further funding in terms of proof-of concept to carry out extensive pre-clinical in vivo studies to develop the field.
 
Description Department web-site 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact In addition to the UCL web-site and Royal Free NHS Trust we have developed our own web-site to disseminate rearch advances to the wider comunity. NHS links

The web-site, http://www.scleroderma-royalfree.org.uk/ recives ~300 hits per month and has direct links to UCL and NHS sityes and other relevant sites of including Patient societies/charities.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
URL http://www.ucl.ac.uk/medicine/
 
Description FLARRE Consortium 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The vision is to promote emerging talent and innovation whilst tackling the key questions relevant to fibrosis and inflammation through investigation, invention and collaboration with industry. The FLARRE Consortium aims to increase understanding of these diseases to ultimately lead to patient benefit.


Promoted the development of a UCL cluster of expertise in fibrosis and infammation. Highlight multidisciplinary skills and promote synergy across UCL. Identify and promote emerging talent (PhD students and young investigators)at UCL. Augment commercial engagement and develop interaction with industry. Enhance international academic collaborations
Year(s) Of Engagement Activity 2013,2014
URL http://www.ucl.ac.uk/flarre
 
Description Hospital News Letter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Twice yearly news letters (Spring and Winter) are sent our to ~4,000 patients and their relative. News letters cover the research and clincial activities taking place in the Department, and major advances as well as new staff recruitments, new awards for research and new and exciting areas of study.

Feed back in terms of correspondcne to the Department, visits to the laboratories and attendance at our once-a-year open day.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
URL http://www.scleroderma-royalfree.org.uk/
 
Description Hospital Open Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Attended by ~100 people including the public, patients and their relatives, patient groups and other health porfessionals including Doctors and Nurses and Occupational Therapists.

Patients and their relatives and members of the public visited the laboratory
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
URL http://www.scleroderma-royalfree.org.uk/
 
Description Wellcome Trust - Fibrosis Meeting: Tissue Fibrosis: State-of-the-Art and Overcoming Roadblocks to Translation 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Fibrosis , the formation of excess fibrous connective tissue, is a global health concern. In response to repetitive injury or inflammation, this pathological scarring process ultimately leads to disordered tissue architecture and impairment of organ function. The meeting was highly interactive discussing fibrosis, models of fibrosis, discovering meaningful biomarkers, matrix biology, potential immunological targets and current challenges in the field.

Development of a UK wide Network for Fibrosis
Setting up a a Web-based portal 'Technology Expertise Sharing Network'
Year(s) Of Engagement Activity 2014
URL https://www.wellcometrustevents.org/WELLCOME/media/uploaded/EVWELLCOME/event_305/Final%20agenda%20-%...