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.
|Maitra, Dhiman; Ali, Iyad; Abdulridha, Rasha M et al. (2014) Kinetic studies on the reaction between dicyanocobinamide and hypochlorous acid. PLoS One 9:e110595|
|Bai, Guangxing; Hock, Thomas D; Logsdon, Naomi et al. (2014) A far-upstream AP-1/Smad binding box regulates human NOX4 promoter activation by transforming growth factor-?. Gene 540:62-7|
|Hecker, Louise; Logsdon, Naomi J; Kurundkar, Deepali et al. (2014) Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 6:231ra47|
|Abu-Soud, Husam M; Maitra, Dhiman; Shaeib, Faten et al. (2014) Disruption of heme-peptide covalent cross-linking in mammalian peroxidases by hypochlorous acid. J Inorg Biochem 140:245-54|
|Lakshminrusimha, Satyan; Suresh, Madathilparambil V; Knight, Paul R et al. (2013) Role of pulmonary artery reactivity and nitric oxide in injury and inflammation following lung contusion. Shock 39:278-85|
|Suresh, Madathilparambil V; Yu, Bi; Lakshminrusimha, Satyan et al. (2013) The protective role of MnTBAP in oxidant-mediated injury and inflammation in a rat model of lung contusion. Surgery 154:980-90|
|Maitra, Dhiman; Shaeib, Faten; Abdulhamid, Ibrahim et al. (2013) Myeloperoxidase acts as a source of free iron during steady-state catalysis by a feedback inhibitory pathway. Free Radic Biol Med 63:90-8|
|Abu-Soud, Husam M; Maitra, Dhiman; Byun, Jaeman et al. (2012) The reaction of HOCl and cyanocobalamin: corrin destruction and the liberation of cyanogen chloride. Free Radic Biol Med 52:616-25|
|Li, Hong; Cao, Zehong; Moore, D Ray et al. (2012) Microbicidal activity of vascular peroxidase 1 in human plasma via generation of hypochlorous acid. Infect Immun 80:2528-37|
|Hinz, Boris; Phan, Sem H; Thannickal, Victor J et al. (2012) Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 180:1340-55|
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