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    Strategies to Target the Bone Morphogenetic Protein Signalling Pathway in Lung Disease


    Purcell, James (2011) Strategies to Target the Bone Morphogenetic Protein Signalling Pathway in Lung Disease. PhD thesis, National University of Ireland Maynooth.

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    Abstract

    Lung disease and lung injury are responsible for 20% of deaths of the Irish population every year, and the country has the 2nd highest death rate in Europe for respiratory diseases. Conditions related to the respiratory system are the second largest long term illness by young adults. Lung cancer is the largest cause of cancer related death in Europe as a whole. New and refined mechanisms of drug delivery for the prevention, cure or delayed progression of disease, represents a pathway for the delivery of novel style therapies and for the targeted delivery of different of more toxic drugs to the airways in order to increase efficiency of both the delivery mechanism and of the drug utilised. Here we looked at the use of a number of different mechanisms, which can be used as stand-alone devices/delivery agents and/or in conjunction with other devices and delivery agents to optimise targeted delivery to the lung, and to the specific areas required. We examined the use of a direct delivery mechanism, particle bombardment, for the delivery of various molecules to human and murine cells lines, and to mouse primary cell isolates, MAECs, to examine the potential of the mechanism for adaption to a clinical mechanism for delivery. An aerosol delivery system was developed to utilise a current aerosol generator for the delivery of aerosol to mice in vivo. This was done with the aim of creating a more efficacious and ergonomic mechanism for the delivery of aerosols to mice in vivo and also to investigate the effects of aerosolistation on various drug compound molecules. We also looked for BMP4 disregulation in a number of different animal models to help ascertain the role of the pathway in the progression of disease and damage in the lung. BMP4 has been shown to have a role in the induction of EMT in MAECS (E.Molloy) and to play a role in both lung cancer and allergic Rhinitis. Here we looked at its role in a number of different models. It was firstly examined in vitro in mouse cell lines and primary cell isolates and the effect of pathway stimulation and deregulation examined. The role of the pathway was then examined in both a murine Elastase model of emphysema, where it was determined to be inactive, and a murine OVA model of asthma where deregulation of the active pathway was evident. The pathway was also shown to be activated in a deregulated fashion in an Ozone/HDMA model of allergic asthma in Rhesus Macaques. In vitro models of mouse, human and primate cells lines were used to examine the role of BMP4 in more detail. Mouse cell lines and primary isolates were used both in normal culture and in an air liquid interface (ALI), stimulated with BMP4 and examined. An air liquid interface enables the culturing of cells in a system consistent with that of the in vivo environment, where the nutrition is provided through the basal surface of the cells and the dorsal surfaces of the cells are exposed to air. Murine model of OVA induced asthma in vivo was also stimulated with exogenous BMP4 and the effects monitored. Human primary cells and primate primary cell isolates were also grown in ALI and were treated with either BMP4 or EGTA and BMP4 in order to help determine more information about the cells involved in the pathway and the other pathways that are recruited by BMP activation.

    Item Type: Thesis (PhD)
    Keywords: Bone Morphogenetic; Protein Signalling; Lung Disease;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 4216
    Depositing User: IR eTheses
    Date Deposited: 21 Feb 2013 09:56
    URI:

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