Functional characterisation of the major susceptibility locus (PSORS1) for cutaneous inflammation in psoriasis

Lead Research Organisation: King's College London
Department Name: Genetics and Molecular Medicine

Abstract

Skin presents an essential barrier to environmental triggers capable of preventing challenge to the bodies natural defence mechanisms which includes a sophisticated immune surveillance network. Psoriasis, a life long skin disorder, is amongst a group of common conditions associated with chronic irritation and inflammation. Available evidence points to a fundamental defect in the capacity for barrier protection, dysregulation of the immune network or a combination of these through abnormal communication between skin and immune pathways. In order to develop new and effective therapies, a clear understanding of these processes and the fundamental defects that characterise the risk of developing psoriasis is now required. From a well defined region of the human genome, we have set out a series of studies designed to characterise the primary alterations that generate a very much increased risk disease development. Progress towards more effective ways to prevent or cure psoriasis would be expected to cut both in the short and long term, the heavy burden of chronic inflammation, and thus lead to a significant health and economic benefits compared to the present management of this disorder.

Technical Summary

Psoriasis, a disorder characterised by chronic cutaneous inflammation is amongst the most significant health care problems in dermatological practice. Our group has been instrumental in the identification and delineation of the location of the major genetic risk factor for disease susceptibility, known as PSORS1 and in describing the critical role of T lymphocytes in disease pathogenesis. In order to correctly target therapeutic strategies that form part of our translational research programme, we now need to precisely identify a) the primary molecular defect underlying PSORS1 conferred susceptibility and b) the cellular types, dysregulation of which are key to disease development. Epithelial (keratinocytes) and lymphoid effector cells are prime candidates, as both are known, from our work in human and model systems, to be critical to disease expression and progression. However, we now need to establish the primacy of these cell types on a more physiological basis in the context of our previous genetic studies. To accomplish this we have established the following set of objectives. (1) We will generate a detailed map of transcriptional activity and regulators, across the PSORS1 major susceptibility genomic interval (~250kb) and relate these findings to underlying genetic variation, (2) we will perform functional studies of the two principle biological candidate genes within this region, namely the Class 1 immune recognition molecule, HLA C and CDSN encoding the epithelial junctional protein, corneodesmosin and (3) we will validate our studies through targeted mutagenesis of the PSORS 1 interval in an established in vivo model system. Taken together, these studies will deliver fundamental insights as to the aetiology of common chronic cutaneous inflammation and define the relationship between epithelial and lymphoid dysregulation that leads to the development of psoriasis.

Publications

10 25 50
 
Description MRC Clinical Training Fellowship
Amount £199,657 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2013 
End 07/2016
 
Description MRC Clinical Training Fellowship
Amount £244,510 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 10/2011
 
Description MRC Stratified Medicine award
Amount £2,500,000 (GBP)
Funding ID MR/L011808/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2014 
End 04/2018
 
Description MRC clinical training fellowship
Amount £207,536 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2010 
End 08/2013
 
Description MRC clinical training fellowship
Amount £231,159 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2007 
End 10/2010
 
Description PhD studentships
Amount £81,000 (GBP)
Funding ID 3007s 
Organisation British Skin Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Psoriasis Association PhD studentship
Amount £75,000 (GBP)
Organisation The Psoriasis Association 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 10/2015
 
Title BACS 
Description generation of a series of BAC library which harbours using DNA derived from an individual heterozygous for the HLA-Cw0602 risk allele for psoriasis 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Allowed detailed analysis of potential causal variants responsible for the susceptibility to psoriasis associated with this locus. 
 
Title HLA-C promoter constructs 
Description HLA-C allele specific reporter constructs 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact identification of a promoter variant mediating reduced responsiveness to TNF-a 
 
Title bisulphite NGS 
Description Design of MHC specific array for targeted bisulphite next generation sequencing (NGS) and optimisation of NGS techniques and analysis for application to this specific protocol 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Successful application of this technique to the highly variable MHC region 
 
Title immunochip 
Description SNP array designed to include variants relevant to immunological disease including variants identified through this project to be potential causal variants in psoriasis 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact experimental work currently on going. 
 
Title knockdown cell lines 
Description Two Immortalized keratinocyte cell lines where a gene associated with pustular psoriasis has been knocked down by lentiviral shRNA transduction 
Type Of Material Cell line 
Provided To Others? No  
Impact The characterization of the cellular phenotype will be included in a gene identification manuscript, which is currently in preparation. 
 
Description GAIN psoriasis consortium 
Organisation University of Kiel
Country Germany 
Sector Academic/University 
PI Contribution planning of experimental design and analyitcal development platforms
Collaborator Contribution sharing of data resourcessharing of data resources
Impact As a new collaboration this is yet to produce outcomes
Start Year 2010
 
Description GAIN psoriasis consortium 
Organisation University of Michigan
Country United States 
Sector Academic/University 
PI Contribution planning of experimental design and analyitcal development platforms
Collaborator Contribution sharing of data resourcessharing of data resources
Impact As a new collaboration this is yet to produce outcomes
Start Year 2010
 
Description MAARS 
Organisation Fios Genomics
Country United Kingdom 
Sector Private 
PI Contribution In-vivo and in-vitro functional assays
Collaborator Contribution Microbiome sequencing; transcriptomics
Impact 5.9 million euros funding from the EU to the MAARS Consortium, where King's College London is represented by Profs Barker and Nestle (both co-investigators in the MRC G0601387 grant)
Start Year 2011
 
Description MAARS 
Organisation Hebrew University of Jerusalem
Country Israel 
Sector Academic/University 
PI Contribution In-vivo and in-vitro functional assays
Collaborator Contribution Microbiome sequencing; transcriptomics
Impact 5.9 million euros funding from the EU to the MAARS Consortium, where King's College London is represented by Profs Barker and Nestle (both co-investigators in the MRC G0601387 grant)
Start Year 2011
 
Description MAARS 
Organisation Heinrich Heine University Düsseldorf
Country Germany 
Sector Academic/University 
PI Contribution In-vivo and in-vitro functional assays
Collaborator Contribution Microbiome sequencing; transcriptomics
Impact 5.9 million euros funding from the EU to the MAARS Consortium, where King's College London is represented by Profs Barker and Nestle (both co-investigators in the MRC G0601387 grant)
Start Year 2011
 
Description MAARS 
Organisation Icosagen
Country Estonia 
Sector Private 
PI Contribution In-vivo and in-vitro functional assays
Collaborator Contribution Microbiome sequencing; transcriptomics
Impact 5.9 million euros funding from the EU to the MAARS Consortium, where King's College London is represented by Profs Barker and Nestle (both co-investigators in the MRC G0601387 grant)
Start Year 2011
 
Description MAARS 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution In-vivo and in-vitro functional assays
Collaborator Contribution Microbiome sequencing; transcriptomics
Impact 5.9 million euros funding from the EU to the MAARS Consortium, where King's College London is represented by Profs Barker and Nestle (both co-investigators in the MRC G0601387 grant)
Start Year 2011
 
Description MAARS 
Organisation University of Kiel
Country Germany 
Sector Academic/University 
PI Contribution In-vivo and in-vitro functional assays
Collaborator Contribution Microbiome sequencing; transcriptomics
Impact 5.9 million euros funding from the EU to the MAARS Consortium, where King's College London is represented by Profs Barker and Nestle (both co-investigators in the MRC G0601387 grant)
Start Year 2011
 
Description PSORT 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Genotyping and data analysis
Collaborator Contribution Patient recruitment and phenotyping; transcriptomic analysis.
Impact MRC Stratified Medicine grant
Start Year 2012
 
Description PSORT 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Genotyping and data analysis
Collaborator Contribution Patient recruitment and phenotyping; transcriptomic analysis.
Impact MRC Stratified Medicine grant
Start Year 2012
 
Description PSORT 
Organisation The Psoriasis Association
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Genotyping and data analysis
Collaborator Contribution Patient recruitment and phenotyping; transcriptomic analysis.
Impact MRC Stratified Medicine grant
Start Year 2012
 
Description PSORT 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Genotyping and data analysis
Collaborator Contribution Patient recruitment and phenotyping; transcriptomic analysis.
Impact MRC Stratified Medicine grant
Start Year 2012
 
Description PSORT 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Genotyping and data analysis
Collaborator Contribution Patient recruitment and phenotyping; transcriptomic analysis.
Impact MRC Stratified Medicine grant
Start Year 2012
 
Description The impact of Histone deacetylation inhibition on inflammation 
Organisation Dana-Farber Cancer Institute
Country United States 
Sector Hospitals 
PI Contribution testing HDACi in a mouse model of inflammation
Collaborator Contribution intellectual and experimental input
Impact replication of results underway
Start Year 2008
 
Description UCSF 
Organisation University of California, San Francisco
Department Department of Neurological Surgery
Country United States 
Sector Academic/University 
PI Contribution experimental work and design
Collaborator Contribution training in experimental and analysis techniques
Impact experimental work still under way.
Start Year 2011
 
Description Van Heel 
Organisation Queen Mary University of London
Department Centre for Statistics (QMUL)
Country United Kingdom 
Sector Academic/University 
PI Contribution DNA samples, data analysis
Collaborator Contribution Study design and data generation
Impact Article by Hunt et al, recently published on Nature
Start Year 2012
 
Description WTCCC2 
Organisation Wellcome Trust
Department Wellcome Trust Case Control Consortium 2
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Samples, analysis, expertise
Collaborator Contribution Genotyping, analysis, expertise
Impact Joint publications Strange et al, Nat Genet. 2010 Nov;42(11):985-90. Epub 2010 Oct 17.PMID: 20953190 Tsoi et al, Nat Genet. 2012 Nov 11. doi: 10.1038/ng.2467. [Epub ahead of print] PMID: 23143594
Start Year 2008
 
Description psoriasis immunochip consortium 
Organisation University of Kiel
Country Germany 
Sector Academic/University 
PI Contribution data and information sharing
Collaborator Contribution data and information sharingdata and information sharing
Impact identification of psoriasis relevant variants to include on the Immunochip
Start Year 2010
 
Description psoriasis immunochip consortium 
Organisation University of Michigan
Country United States 
Sector Academic/University 
PI Contribution data and information sharing
Collaborator Contribution data and information sharingdata and information sharing
Impact identification of psoriasis relevant variants to include on the Immunochip
Start Year 2010
 
Description biomedical research forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact NIHR Biomedical Research Centre - monthly open access presentation transmitted to 4 sites in London and internationally.

increased awareness of aims of research
Year(s) Of Engagement Activity 2008,2009,2010,2011,2013
 
Description cafe scientifique 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact short presentation to members of the public at the Biomedical Research Centre cafe scientifique event at Guy's Hospital, London. Questions and discussions followed

Positive feed back received
Year(s) Of Engagement Activity 2010