Mechanism of neutrophil elastase induced pulmonary fibrosis: the role of alphavbeta6 integrin mediated TGFbeta activation. (360G-Wellcome-085350_Z_08_Z)

£280,719

Idiopathic pulmonary fibrosis is characterised by excessive matrix deposition within the lungs. We have recently shown that neutrophil elastase null (ne-/-) mice are protected from bleomycin induced matrix depostion due to a failure to activate TGFbeta. NE can proteolytically cleave TGFbeta from extracellular matrix in vitro, but whether this leads to active TGFbeta in vivo is unknown. We have data demonstrating that NE can also initiate intracellular signalling pathways that activate TGFbeta, v ia the TLR4 receptor. We will investigate the hypothesis that NE induces alphavbeta6 mediated TGFbeta activation via a TLR4 and RhoA mediated pathway, promoting collagen deposition in the lung. Specifically, we will determine the pathway through which NE induces alphavbeta6 integrin mediated TGFbeta activation in epithelial cells. Using models of injury in ne-/- and slpi-/- (SLPI is an inhibitor of NE) mice we will identify whether NE can signal to the alphavbeta6 integrin in the lung and whethe r this pathway is responsible for the protection from lung fibrosis observed in ne-/- mice. We will thus determine whether the fibrogenic effects of NE are mediated via the alphavbeta6 integrin, aiding the development of therapies that target active TGFbeta at sites of inflammation.

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Grant Details

Amount Awarded 280719
Applicant Surname Jenkins
Approval Committee Physiological Sciences Funding Committee
Award Date 2008-07-08T00:00:00+00:00
Financial Year 2007/08
Grant Programme: Title Project Grant
Internal ID 085350/Z/08/Z
Lead Applicant Prof Richard Jenkins
Other Applicant(s) Prof Geoffrey Laurent
Partnership Value 280719
Planned Dates: End Date 2011-10-31T00:00:00+00:00
Planned Dates: Start Date 2008-11-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East Midlands