Host defence peptides and their role in inflammation in the respiratory tract

Lead Research Organisation: MRC Human Genetics Unit

Abstract

Death from respiratory disease in the UK is twice the EU average. Illnesses such as lung cancer, asthma, pneumonia and chronic obstructive pulmonary disease are now killing more people in the UK than coronary heart disease. Cystic fibrosis is an inherited condition and results in premature death from lung disease as a result of repeated airway infections. The predominance of multi resistance superbugs makes the illness more difficult to treat and limits the quality of life of affected individuals.||Recently I have identified several naturally occurring small antibiotic molecule that are effective at killing several important superbugs. I wish to understand how this molecule kills bacteria and whether this will help the design of new antibiotics for use in the clinic.||I am also interested in how these host defence peptides are involved in inflammation and what function they have in addition to being antimicrobials.

Technical Summary

Death from respiratory disease in the UK is twice the EU average and is now killing more people in the UK than coronary heart disease. Cystic fibrosis is a genetic disease that results in premature death from lung disease precipitated by chronic microbial infection and inflammation. The predominance of multi resistance superbugs exacerbates the condition and limits the quality of life of affected individuals. ||My research aims to relate genes involved in the innate immune response to the destructive effects of inflammation. In particular I am focussing on ?-defensin genes which are host defence peptides that link the innate and adaptive immune responses. The ?-defensin gene cluster is highly copy number variable and increase or decrease in copy number has been implicated in inflammatory disease including Psoriasis and Crohns disease. In vitro they are both antimicrobial and are chemoattractant for monocytes, CD4+ T cells and immature dendritic cells. I wish to understand the function of these peptides using in vivo models (mice and zebrafish) and to relate structure and function. We hope to use this information to design novel peptides with immunomodulatory activity.

Publications

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Dorin JR (2007) Genetics. Beta-defensin repertoire expands. in Science (New York, N.Y.)

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Macmillan D (2011) Synthesis of cyclic peptides through an intramolecular amide bond rearrangement. in Chembiochem : a European journal of chemical biology

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McCullough B (2006) Characterisation of DEFB107 by mass spectrometry: Lessons from an anti-antimicrobial defensin in International Journal of Mass Spectrometry

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Reynolds NL (2010) Peptide fragments of a beta-defensin derivative with potent bactericidal activity. in Antimicrobial agents and chemotherapy

 
Description Genetical Society vacation studentship
Amount £2,500 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2011 
End 08/2011
 
Description AGS 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided ES cell technology to create mouse models for AGS and innate immunity resource provision and advice
Collaborator Contribution Provision of reagents useful in research and collaborator contacts
Impact creation of several AGS mouse lines ready for Andrew Jackson group to analyse
Start Year 2006
 
Description BH and LL 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution mouse models for limb dysmorphology
Collaborator Contribution targeting constructs for ES cell manipulation of genome
Impact series of mutant lines allowing characterization of zrs in mouse
 
Description BH joint PhD student 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution generation of mutant mice for RA research relevant to limb
Collaborator Contribution joint PhD student
Impact mutant mice and papers in preparation
Start Year 2008
 
Description GM peptides 
Organisation University of California, Santa Cruz
Department Chemistry & Biochemistry Faculty
Country United States 
Sector Academic/University 
PI Contribution functional characterization of novel peptides
Collaborator Contribution Novel synthetic peptide reagents of significant value
Impact paper submitted
Start Year 2010
 
Description H1n1 Flu 
Organisation University of Edinburgh
Department The Roslin Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution I provide peptide and they do flu protection assays
Collaborator Contribution is doing animal experiments with flu virus for us
Impact data has been generated
Start Year 2011
 
Description Team Defensin 
Organisation University College London
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution monthly meetings and responsibility of the molecular genetics of b-defensin gene cluster. Evolutionary analyses, antibactericidal assays, chemotaxis, preparation of manuscripts for publication
Collaborator Contribution synthesis and analysis of host derived peptides.production of biologically active peptidesprovided training and clinically relevant bacterial strains
Impact publications 17353239, 18180295, 18627133, 19404978, 19519528, 19907782, 20102218, 20022113, 20336257, 20176896
 
Description Team Defensin 
Organisation University of Edinburgh
Department Department of Medical Microbiology
Country United Kingdom 
Sector Academic/University 
PI Contribution monthly meetings and responsibility of the molecular genetics of b-defensin gene cluster. Evolutionary analyses, antibactericidal assays, chemotaxis, preparation of manuscripts for publication
Collaborator Contribution synthesis and analysis of host derived peptides.production of biologically active peptidesprovided training and clinically relevant bacterial strains
Impact publications 17353239, 18180295, 18627133, 19404978, 19519528, 19907782, 20102218, 20022113, 20336257, 20176896
 
Description Team Defensin 
Organisation University of Edinburgh
Department School of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution monthly meetings and responsibility of the molecular genetics of b-defensin gene cluster. Evolutionary analyses, antibactericidal assays, chemotaxis, preparation of manuscripts for publication
Collaborator Contribution synthesis and analysis of host derived peptides.production of biologically active peptidesprovided training and clinically relevant bacterial strains
Impact publications 17353239, 18180295, 18627133, 19404978, 19519528, 19907782, 20102218, 20022113, 20336257, 20176896
 
Description Team immunomodulation 
Organisation University of Edinburgh
Department MRC Centre for Inflammation Research
Country United Kingdom 
Sector Academic/University 
PI Contribution carrying out in vivo and in vitro murine experiments, evolutionary analyses, writing manuscript for publication
Collaborator Contribution carrying out experiments on human subject samples, provision of reagents, regular meetings.
Impact publication 20104491
Start Year 2008
 
Description coat colour investigation 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution innate immunity knowledge, transgenic mice
Collaborator Contribution knowledge and mouse resources for coat colour investigation
Impact publication 18048676
Start Year 2007
 
Description team eczema 
Organisation University of Edinburgh
Department Department of Dermatology
Country United Kingdom 
Sector Academic/University 
PI Contribution provision of mouse model for atopic dermatitis
Collaborator Contribution part time visiting researcher in lab
Impact establishment of flaky tail colony. Placement of clinician doing MD in my lab part time for 1 year.
Start Year 2008
 
Description zebrafish 
Organisation Cancer Research UK
Department Edinburgh Cancer Research UK Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution advice on immunology and student direction
Collaborator Contribution advice to joint PhD student, joint PhD student and access to zebrafish facilities etc.
Impact publication 19133827
Start Year 2007
 
Description Dunbar Science Club presentation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 60 children attended the workshops on Saturday morning in May and made DNA from lentils, made DNA models, did activity to demonstrate cell division.

Interest in Science in local schools is extremely high
Year(s) Of Engagement Activity 2014
URL http://www.dunbarscienceclub.org.uk/?p=930
 
Description Dunbar Science Festival 2012 and 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact Many interested children and parents. Over the two days the festival had 5000 visitors and we had 300 children making DNA and making sweetie DNA helix. 2013 did genetics of red hair using Harry Potter families to demonstrate inheritance. Invited back to represent Science festival at another community fayre event.

Interest in Science strong in Dunbar and we were asked back to 2013 festival and to plan a workshop for the Science club.
Year(s) Of Engagement Activity 2012,2013
URL http://dunbarscifest.org.uk/
 
Description hosted two summer students on nuffield bursaries 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact hosting school student over summer to do a project in the lab and they were paid a bursary by the Nuffield Summer Bursary Scheme.

Each year a poster of each student's projects is then presented at the celebration event either in Glasgow or Edinburgh.
Year(s) Of Engagement Activity 2007,2009
 
Description school visit- Dunbar 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact speaking to 6th formers about my research and their University course choices

teacher reported more interest in Biology at University as a study choice
Year(s) Of Engagement Activity 2007,2008