Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease
Chronic Obstructive Pulmonary Disease (COPD) is the third commonest cause of death worldwide. Its natural course is a decline in lung function, punctuated by exacerbations, leading to premature death. COPD pathogenesis remains incompletely understood. The disease is widely accepted to result from an...
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| Format: | Thesis (University of Nottingham only) |
| Language: | English |
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2015
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| Online Access: | https://eprints.nottingham.ac.uk/74156/ |
| _version_ | 1848800845912604672 |
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| author | Mallia-Milanes, Brendan |
| author_facet | Mallia-Milanes, Brendan |
| author_sort | Mallia-Milanes, Brendan |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Chronic Obstructive Pulmonary Disease (COPD) is the third commonest cause of death worldwide. Its natural course is a decline in lung function, punctuated by exacerbations, leading to premature death. COPD pathogenesis remains incompletely understood. The disease is widely accepted to result from an excess protease over protective anti-protease activity, leading to extracellular matrix (ECM) damage in the lungs. However, this belief is oversimplified since both harmful pro-inflammatory and protective anti-inflammatory roles are now described for proteases in animal and cell culture models. Matrix Metalloproteinase (MMP)-12 was originally implicated in COPD by its degradation of elastin in the lung ECM. However, newer in vitro evidence reveals MMP-12 to target substrates outside the ECM. Given these newer findings it was hypothesized that MMP-12 cleaves non-ECM proteins in COPD which may contribute to the disease process. This hypothesis was addressed initially using a candidate-based approach, by testing osteopontin and tissue factor pathway inhibitor as potential MMP-12 substrates. However, these proved to be neutrophil elastase targets. Next, a novel proteomic technique called TAILS (Terminal Amine Isotopic Labelling of Substrates) was employed to identify potential MMP-12 substrates using a Mmpl2-/-smoking mouse model. This led to the discovery of new non-ECM MMP-12 substrates in the mouse model. Next, these findings were translated to human COPD sputum to identify potential MMP-12 targets in COPD, both at exacerbation and during stable disease. Similarly, within human COPD sputum non-ECM MMP-12 substrates were discovered, of particular interest, complement factor C3 and the anticoagulant anti-thrombin III, revealing ever new potential roles for MMP-12 in COPD. |
| first_indexed | 2025-11-14T20:58:02Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-74156 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:58:02Z |
| publishDate | 2015 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-741562025-02-28T12:27:28Z https://eprints.nottingham.ac.uk/74156/ Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease Mallia-Milanes, Brendan Chronic Obstructive Pulmonary Disease (COPD) is the third commonest cause of death worldwide. Its natural course is a decline in lung function, punctuated by exacerbations, leading to premature death. COPD pathogenesis remains incompletely understood. The disease is widely accepted to result from an excess protease over protective anti-protease activity, leading to extracellular matrix (ECM) damage in the lungs. However, this belief is oversimplified since both harmful pro-inflammatory and protective anti-inflammatory roles are now described for proteases in animal and cell culture models. Matrix Metalloproteinase (MMP)-12 was originally implicated in COPD by its degradation of elastin in the lung ECM. However, newer in vitro evidence reveals MMP-12 to target substrates outside the ECM. Given these newer findings it was hypothesized that MMP-12 cleaves non-ECM proteins in COPD which may contribute to the disease process. This hypothesis was addressed initially using a candidate-based approach, by testing osteopontin and tissue factor pathway inhibitor as potential MMP-12 substrates. However, these proved to be neutrophil elastase targets. Next, a novel proteomic technique called TAILS (Terminal Amine Isotopic Labelling of Substrates) was employed to identify potential MMP-12 substrates using a Mmpl2-/-smoking mouse model. This led to the discovery of new non-ECM MMP-12 substrates in the mouse model. Next, these findings were translated to human COPD sputum to identify potential MMP-12 targets in COPD, both at exacerbation and during stable disease. Similarly, within human COPD sputum non-ECM MMP-12 substrates were discovered, of particular interest, complement factor C3 and the anticoagulant anti-thrombin III, revealing ever new potential roles for MMP-12 in COPD. 2015 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en arr https://eprints.nottingham.ac.uk/74156/1/716487.pdf Mallia-Milanes, Brendan (2015) Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease. PhD thesis, University of Nottingham. |
| spellingShingle | Mallia-Milanes, Brendan Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease |
| title | Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease |
| title_full | Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease |
| title_fullStr | Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease |
| title_full_unstemmed | Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease |
| title_short | Identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease |
| title_sort | identifying matrix metalloproteinase-12 substrates as therapeutic targets in chronic obstructive pulmonary disease |
| url | https://eprints.nottingham.ac.uk/74156/ |