The role of TIMP3 and TIMP3 polymorphisms in the inflammatory and fibrotic events observed in interstitial lung disease. (360G-Wellcome-080321_Z_06_Z)

Pulmonary fibrosis represents the end stage of a heterogeneous group of interstitial lung diseases (ILD) with poor prognosis and no effective treatment. The pathogenesis of ILD is incompletely understood however, a marked change in the normal balance of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) occurs. The host centre has reported that TIMP3 polymorphisms appear protective against susceptibility to pigeon breeders' disease. I also have data suggesting they influence susceptibility to sarcoidosis. TIMP3 may play key roles in the regulation of inflammation, apoptosis and fibroproliferation. However, the relative importance of TIMP3 in the various stages of ILD and therole of TIMP3 polymorphisms is unknown. I hypothesise that TIMP3 contributes to the pathogenesis of ILDs through effects on inflammatory and fibrotic processes and that functional polymorphisms in the TIMP3 gene will influence these processes. To address this hypothesis I will identify and determine the function of TIMP3 polymorphisms relevant to ILD. I will also examine the effect of TIMP3 deficiency on lung injury and fibrosis in an animal model of lung fibrogenesis. These studies will provide fundamental information on the role of TIMP3 in ILD. It may enable subjects 'at risk of disease to be identified and ultimately lead to new targets for intervention.