Humans with Idiopathic pulmonary fibrosis (IPF) are at a high risk for progressive respiratory failure, acute exacerbations of the disease and death. There is a recognized need for novel mechanism-based biomarkers that accurately predict pathways activated in the individuals with progressive IPF and those that are likely to be more responsive to specific therapies. This proposal is in response to a request of application (RFA-HL-08- 001) and directly addresses this critical gap in our diagnostic capability. The overall goals of this proposal are to develop and validate novel biomarkers using a mass spectrometry (MS)-based approach followed by a microarray-based proteomic platform combined with MS to elucidate pathways that contribute to IPF progression. A major focus of the proposal will involve development of a microarray-based proteomic platform that can readily be transferred to high throughput clinical applications. Using highly sensitive and specific gas chromatography MS we have recently characterized and validated specific markers of oxidative stress in human plasma. These markers serve as molecular fingerprints for specific oxidation pathways. We have also developed a novel microarray based proteomic platform that can accurately identify and screen modified proteins from the plasma proteome. We predict that using our novel approach we will be able to identify differential oxidation of plasma proteins which uniquely identifies subsets of IPF patients at risk for progressive disease and those likely to benefit from redox-modulating drug therapies.
IPF is a progressive and ultimately fatal disease for which no effective drug therapies currently exist. Finding effective therapies for this disease has been limited by the lack of reliable biomarkers of disease activity/progression. Heterogeneity in responsiveness to specific treatments may also limit the ability to demonstrate effectiveness of a particular treatment strategy. This study will define novel plasma biomarkers in IPF patients with progressive disease and identify specific patient subgroups that respond favorably to redox- modulating drug therapy.
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