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Advancing the high throughput identification of liver fibrosis protein signatures using multiplexed ion mobility spectrometry.

ABSTRACT: Rapid diagnosis of disease states using less invasive, safer, and more clinically acceptable approaches than presently employed is a crucial direction for the field of medicine. While MS-based proteomics approaches have attempted to meet these objectives, challenges such as the enormous dynamic range of protein concentrations in clinically relevant biofluid samples coupled with the need to address human biodiversity have slowed their employment. Herein, we report on the use of a new instrumental platform that addresses these challenges by coupling technical advances in rapid gas phase multiplexed ion mobility spectrometry separations with liquid chromatography and MS to dramatically increase measurement sensitivity and throughput, further enabling future high throughput MS-based clinical applications. An initial application of the liquid chromatography--ion mobility spectrometry-MS platform analyzing blood serum samples from 60 postliver transplant patients with recurrent fibrosis progression and 60 nontransplant patients illustrates its potential utility for disease characterization.

SUBMITTER: Baker ES

PROVIDER: S-EPMC3977189 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Advancing the high throughput identification of liver fibrosis protein signatures using multiplexed ion mobility spectrometry.

Baker Erin Shammel ES Burnum-Johnson Kristin E KE Jacobs Jon M JM Diamond Deborah L DL Brown Roslyn N RN Ibrahim Yehia M YM Orton Daniel J DJ Piehowski Paul D PD Purdy David E DE Moore Ronald J RJ Danielson William F WF Monroe Matthew E ME Crowell Kevin L KL Slysz Gordon W GW Gritsenko Marina A MA Sandoval John D JD Lamarche Brian L BL Matzke Melissa M MM Webb-Robertson Bobbie-Jo M BJ Simons Brenna C BC McMahon Brian J BJ Bhattacharya Renuka R Perkins James D JD Carithers Robert L RL Strom Susan S Self Steven G SG Katze Michael G MG Anderson Gordon A GA Smith Richard D RD

Molecular & cellular proteomics : MCP 20140108 4

Rapid diagnosis of disease states using less invasive, safer, and more clinically acceptable approaches than presently employed is a crucial direction for the field of medicine. While MS-based proteomics approaches have attempted to meet these objectives, challenges such as the enormous dynamic range of protein concentrations in clinically relevant biofluid samples coupled with the need to address human biodiversity have slowed their employment. Herein, we report on the use of a new instrumental ...[more]

PMID: 24403597

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Project description:RationaleThe monitoring of TB treatments in clinical practice and clinical trials relies on traditional sputum-based culture status indicators at specific time points. Accurate, predictive, blood-based protein markers would provide a simpler and more informative view of patient health and response to treatment.ObjectiveWe utilized sensitive, high throughput multiplexed ion mobility-mass spectrometry (IM-MS) to characterize the serum proteome of TB patients at the start of and at 8 weeks of rifamycin-based treatment. We sought to identify treatment specific signatures within patients as well as correlate the proteome signatures to various clinical markers of treatment efficacy.MethodsSerum samples were collected from 289 subjects enrolled in CDC TB Trials Consortium Study 29 at time of enrollment and at the end of the intensive phase (after 40 doses of TB treatment). Serum proteins were immunoaffinity-depleted of high abundant components, digested to peptides and analyzed for data acquisition utilizing a unique liquid chromatography IM-MS platform (LC-IM-MS). Linear mixed models were utilized to identify serum protein changes in the host response to antibiotic treatment as well as correlations with culture status end points.ResultsA total of 10,137 peptides corresponding to 872 proteins were identified, quantified, and used for statistical analysis across the longitudinal patient cohort. In response to TB treatment, 244 proteins were significantly altered. Pathway/network comparisons helped visualize the interconnected proteins, identifying up regulated (lipid transport, coagulation cascade, endopeptidase activity) and down regulated (acute phase) processes and pathways in addition to other cross regulated networks (inflammation, cell adhesion, extracellular matrix). Detection of possible lung injury serum proteins such as HPSE, significantly downregulated upon treatment. Analyses of microbiologic data over time identified a core set of serum proteins (TTHY, AFAM, CRP, RET4, SAA1, PGRP2) which change in response to treatment and also strongly correlate with culture status. A similar set of proteins at baseline were found to be predictive of week 6 and 8 culture status.ConclusionA comprehensive host serum protein dataset reflective of TB treatment effect is defined. A repeating set of serum proteins (TTHY, AFAM, CRP, RET4, SAA1, PGRP2, among others) were found to change significantly in response to treatment, to strongly correlate with culture status, and at baseline to be predictive of future culture conversion. If validated in cohorts with long term follow-up to capture failure and relapse of TB, these protein markers could be developed for monitoring of treatment in clinical trials and in patient care.

Dataset Information

Advancing the high throughput identification of liver fibrosis protein signatures using multiplexed ion mobility spectrometry.

Publications

Advancing the high throughput identification of liver fibrosis protein signatures using multiplexed ion mobility spectrometry.

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