Dataset Information

Human serum from patients at multiple time points after ischemic stroke

ABSTRACT: Application of acute therapies such as thrombolysis for ischemic stroke (IS) is constrained because of diagnostic uncertainty and the dynamic nature of stroke biology. To investigate changes in blood proteins after stroke and as a result of thrombolysis treatment we performed label-free quantitative proteomics on serum samples using high resolution mass spectrometry and long HPLC gradient (5 hours) combined with a 50cm column to optimize the peptide separation. We identified (FDR: 1%) and quantified a total of 574 protein groups from a total of 92 samples from 30 patients. Ten patients were treated by thrombolysis as part of a randomised placebo controlled trial and up to five samples were collected from each individual at different time points after stroke. We identified 26 proteins differently expressed by treatment group (FDR: 5%) and significant changes of expression over time for 23 proteins (FDR: 10%). Molecules such as fibrinogen and CRP showed expression profiles with a high potential clinical utility in the acute stroke setting. Protein expression profiles vary acutely in the blood after stroke and have the potential to allow the construction of a stroke clock and to have an impact on IS treatment decision making.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Serum

DISEASE(S): Cerebrovascular Disease

SUBMITTER: Ira Cooke

LAB HEAD: David William Howells

PROVIDER: PXD003218 | Pride | 2018-10-25

REPOSITORIES: Pride

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Publications

Discovery and Longitudinal Evaluation of Candidate Biomarkers for Ischaemic Stroke by Mass Spectrometry-Based Proteomics.

Dagonnier Marie M Cooke Ira Robin IR Faou Pierre P Sidon Tara Kate TK Dewey Helen Margaret HM Donnan Geoffrey Alan GA Howells David William DW

Biomarker insights 20171220

Application of acute therapies such as thrombolysis for ischaemic stroke (IS) is constrained because of diagnostic uncertainty and the dynamic nature of stroke biology. To investigate changes in blood proteins after stroke and as a result of thrombolysis treatment we performed label-free quantitative proteomics on serum samples using high-resolution mass spectrometry and long high-performance liquid chromatography gradient (5 hours) combined with a 50-cm column to optimise the peptide separation ...[more]

PMID: 29308009

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Project description:1. Rationale: Stroke is still a major cause of death and disability worldwide. A better comprehension of stroke pathophysiology is fundamental to reduce its dramatic outcome. The use of high-throughput unbiased omics approaches, such as proteomics and transcriptomics, might aid to deepen the knowledge of stroke at the molecular level. Moreover, the integration of omics data is needed to depict the existing interaction between different molecular units and interpret the results in a global biological context. 2. Objective: Our aim was to identify and verify protein and gene expression changes that occur in the human brain after ischemia through an integrative approach to join and combine the information of both omics analyses. The translational potential of our results was explored in a pilot study with blood samples from ischemic stroke patients. 3. Methods and results: Proteomics and transcriptomics discovery studies were performed in human brain samples from deceased stroke patients, unveiling 128 proteins and 2716 genes significantly dysregulated after cerebral ischemia. Afterwards, integrative bioinformatics analyses joining both datasets exposed several canonical pathways altered in the ischemic area, such as neurotransmitters release or matrisome regulation, highlighting the most influential molecules in these pathways. To conduct the verification phase, 28 genes and 9 proteins were selected to be validated in independent human brain samples by means of orthogonal techniques. Our results were confirmed for NCDN, RAB3C, ST4A1, DNM1L, A1AG1, A1AT, JAM3, VTDB, ANXA1, ANXA2 and IL8. Finally, the blood circulating levels of the validated protein candidates were explored in ischemic stroke patients over the acute phase of the disease. Protein fluctuations along the first week after onset were detected for A1AG1 and A1AT. 4. Conclusion: The results presented here expand the knowledge of stroke pathology, revealing new key molecules that can be further explored as biomarkers and/or therapeutic targets of ischemic stroke.

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