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Prof D Singh, Prof J Vestbo, Dr Simon Lea
No more applications being accepted
About the Project
Chronic obstructive pulmonary disease (COPD) is characterised by persistent airway inflammation, with increased numbers of macrophages and neutrophils. Some patients become colonised with bacteria including Haemophilus influenza and Moraxella catarrhalis. The ability of the innate immune system to clear bacteria is compromised. A subset of COPD patients show eosinophilic airway inflammation, with less presence of bacteria. The treatment of COPD is moving towards a personalised approach, depending on the nature of airway inflammation and the underlying mechanisms responsible.
This project will utilise samples collected from clinical cohorts of early stage and (later stage) severe COPD. The differences in bacteriology and airway inflammation will be studied, in order to better define subtypes of disease present at different stages of COPD. The underlying mechanisms for persistent bacterial colonisation will also be investigated.
The specific aims are (1) To investigate the differences in bacterial colonisation and airway inflammation in early stage compared to severe COPD using sputum and bronchoscopic sampling (2) To develop biomarkers of lung neutrophil activation in COPD patients (3) To identify the mechanisms of susceptibility to infection in COPD patients with persistent bacterial colonisation.
Existing cohorts of COPD patients will be sampled (induced sputum, bronchoscopy, blood), including early stage and severe COPD patients, plus healthy controls. Immunohistochemistry will be performed for inflammatory cell counts, immunoassays will be performed to measure inflammatory mediators such as cytokines and chemokines, proteases (e.g. neutrophil elastase) and breakdown products of tissue degradation. Some of these assays will require validation. Bacteria will be quantified using PCR. Techniques to measure neutrophil activation, and the relationship to bacterial load, will be optimised. Patients with persistent bacterial colonisation will be identified. Microbiology techniques will be used to study species and strain changes, and antibiotic sensitivity. Genetic and biochemical mechanisms of antibiotic resistance will be studied. The ability of COPD macrophages and neutrophils to phagocytose different bacteria will be compared.
This project will utilise samples collected from clinical cohorts of early stage and (later stage) severe COPD. The differences in bacteriology and airway inflammation will be studied, in order to better define subtypes of disease present at different stages of COPD. The underlying mechanisms for persistent bacterial colonisation will also be investigated.
The specific aims are (1) To investigate the differences in bacterial colonisation and airway inflammation in early stage compared to severe COPD using sputum and bronchoscopic sampling (2) To develop biomarkers of lung neutrophil activation in COPD patients (3) To identify the mechanisms of susceptibility to infection in COPD patients with persistent bacterial colonisation.
Existing cohorts of COPD patients will be sampled (induced sputum, bronchoscopy, blood), including early stage and severe COPD patients, plus healthy controls. Immunohistochemistry will be performed for inflammatory cell counts, immunoassays will be performed to measure inflammatory mediators such as cytokines and chemokines, proteases (e.g. neutrophil elastase) and breakdown products of tissue degradation. Some of these assays will require validation. Bacteria will be quantified using PCR. Techniques to measure neutrophil activation, and the relationship to bacterial load, will be optimised. Patients with persistent bacterial colonisation will be identified. Microbiology techniques will be used to study species and strain changes, and antibiotic sensitivity. Genetic and biochemical mechanisms of antibiotic resistance will be studied. The ability of COPD macrophages and neutrophils to phagocytose different bacteria will be compared.
Funding Notes
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
Applicants must be from the UK/EU and funding covers fees/stipend for three years commencing September 2018. Applicants may contact the Primary Supervisor directly with any questions. Online applications must be submitted, select 'Manchester BRC' as the programme - for more information on how to apply please visit https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mbrc-studentships/
Applicants must be from the UK/EU and funding covers fees/stipend for three years commencing September 2018. Applicants may contact the Primary Supervisor directly with any questions. Online applications must be submitted, select 'Manchester BRC' as the programme - for more information on how to apply please visit https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mbrc-studentships/
References
1. Maddi S, Kolsum U, Jackson S, Barraclough R, Maschera B, Simpson KD, Pascal TG, Durviaux S, Hessel EM, Singh D. Ampicillin resistance in Haemophilus influenzae from COPD patients in the UK. Int J Chron Obstruct Pulmon Dis. 2017 May 22;12:1507-1518.
2: Kolsum U, Damera G, Pham TH, Southworth T, Mason S, Karur P, Newbold P, Singh D. Pulmonary inflammation in patients with chronic obstructive pulmonary disease with higher blood eosinophil counts. J Allergy Clin Immunol. 2017 Oct;140(4):1181-1184.
3: Kolsum U, Donaldson GC, Singh R, Barker BL, Gupta V, George L, Webb AJ, Thurston S, Brookes AJ, McHugh TD, Wedzicha JA, Brightling CE, Singh D. Blood and sputum eosinophils in COPD; relationship with bacterial load. Respir Res. 2017 May 8;18(1):88.
4. Bewley MA, Preston JA, Mohasin M, Marriott HM, Budd RC, Swales J, Collini P, Greaves DR, Craig RW, Brightling CE, Donnelly LE, Barnes PJ, Singh D, Shapiro SD, Whyte MKB, Dockrell DH. Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages. Am J Respir Crit Care Med. 2017 Oct 1;196(7):845-855.
2: Kolsum U, Damera G, Pham TH, Southworth T, Mason S, Karur P, Newbold P, Singh D. Pulmonary inflammation in patients with chronic obstructive pulmonary disease with higher blood eosinophil counts. J Allergy Clin Immunol. 2017 Oct;140(4):1181-1184.
3: Kolsum U, Donaldson GC, Singh R, Barker BL, Gupta V, George L, Webb AJ, Thurston S, Brookes AJ, McHugh TD, Wedzicha JA, Brightling CE, Singh D. Blood and sputum eosinophils in COPD; relationship with bacterial load. Respir Res. 2017 May 8;18(1):88.
4. Bewley MA, Preston JA, Mohasin M, Marriott HM, Budd RC, Swales J, Collini P, Greaves DR, Craig RW, Brightling CE, Donnelly LE, Barnes PJ, Singh D, Shapiro SD, Whyte MKB, Dockrell DH. Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages. Am J Respir Crit Care Med. 2017 Oct 1;196(7):845-855.
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