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.
Organisations
- MRC Human Genetics Unit, United Kingdom (Lead Research Organisation)
- Imperial Cancer Research Fund (Collaboration)
- University College London, United Kingdom (Collaboration)
- University of Edinburgh, United Kingdom (Collaboration)
- Medical Research Council (Collaboration)
- University of California, Santa Cruz, United States (Collaboration)
People |
ORCID iD |
| Julia Ruth Dorin (Principal Investigator) |
Publications
Douvaras P
(2012)
Rare corneal clones in mice suggest an age-related decrease of stem cell activity and support the limbal epithelial stem cell hypothesis.
in Stem cell research
Macmillan D
(2011)
Synthesis of cyclic peptides through an intramolecular amide bond rearrangement.
in Chembiochem : a European journal of chemical biology
Semple F
(2011)
Human ß-defensin 3 affects the activity of pro-inflammatory pathways associated with MyD88 and TRIF.
in European journal of immunology
Reynolds NL
(2010)
Peptide fragments of a beta-defensin derivative with potent bactericidal activity.
in Antimicrobial agents and chemotherapy
Tyrrell C
(2010)
Isoleucine/leucine2 is essential for chemoattractant activity of beta-defensin Defb14 through chemokine receptor 6.
in Molecular immunology
De Cecco M
(2010)
Conformational preferences of linear beta-defensins are revealed by ion mobility-mass spectrometry.
in The journal of physical chemistry. B
McCullough BJ
(2010)
Binding a heparin derived disaccharide to defensin inspired peptides: insights to antimicrobial inhibition from gas-phase measurements.
in Physical chemistry chemical physics : PCCP
Semple F
(2010)
Human beta-defensin 3 has immunosuppressive activity in vitro and in vivo.
in European journal of immunology
Vargues T
(2009)
Efficient production of human beta-defensin 2 (HBD2) in Escherichia coli.
in Protein and peptide letters
Kang J
(2009)
Peptide thioester synthesis through N-->S acyl-transfer: application to the synthesis of a beta-defensin.
in Organic & biomolecular chemistry
Taylor K
(2009)
Defensin-related peptide 1 (Defr1) is allelic to Defb8 and chemoattracts immature DC and CD4+ T cells independently of CCR6.
in European journal of immunology
Richardson J
(2008)
mc1r Pathway regulation of zebrafish melanosome dispersion.
in Zebrafish
McCullough BJ
(2008)
Development of an ion mobility quadrupole time of flight mass spectrometer.
in Analytical chemistry
Taylor K
(2008)
Analysis and separation of residues important for the chemoattractant and antimicrobial activities of beta-defensin 3.
in The Journal of biological chemistry
Taylor K
(2007)
Covalent dimer species of beta-defensin Defr1 display potent antimicrobial activity against multidrug-resistant bacterial pathogens.
in Antimicrobial agents and chemotherapy
Dorin JR
(2007)
Genetics. Beta-defensin repertoire expands.
in Science (New York, N.Y.)
MacPherson H
(2006)
Following damage, the majority of bone marrow-derived airway cells express an epithelial marker.
in Respiratory research
McCullough B
(2006)
Characterisation of DEFB107 by mass spectrometry: Lessons from an anti-antimicrobial defensin
in International Journal of Mass Spectrometry
| Description | Genetical Society vacation studentship |
| Amount | £2,500 (GBP) |
| Organisation | The Genetics Society |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2011 |
| 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 |