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Affinity Proteomics Applied to Patient CSF Identifies Protein Profiles Associated with Neuropathic Pain and Fibromyalgia
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden. (Affinity Proteomics)
SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden. (Affinity Proteomics)
SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden. (Affinity Proteomics)
Visa övriga samt affilieringar
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Objective: Today, there are no biological tests on which to base pain diagnoses, treatment choices or to understand the biological processes underlying and accompanying chronic pain for the individual pain patient. Relevant biological markers would greatly aid in diagnosis and treatment of patients with chronic pain. Our study aimed to find proteins in CSF associated with fibromyalgia and neuropathic pain, two common and poorly understood chronic pain conditions.

Methods: We have performed CSF protein profiling of 55 proteins using a 100-plex antibody suspension bead array. We collected, analyzed and compared CSF samples from 25 patients with neuropathic pain (two independent sets, n=14 patients for discovery and n=11 for verification), 40 patients with fibromyalgia and 135 controls without neurological disease from two different populations.

Results: We found significant differences in CSF protein levels between patients and controls (p<0.05). Among these proteins, Apolipoprotein C1 (APOC1) was found to be increased in CSF of neuropathic pain patients compared to controls and there was a non-significant trend for increased levels also in fibromyalgia patient CSF. Ectonucleotide pyrophosphatase (ENPP2, Autotaxin) was increased in the CSF of fibromyalgia patients compared to all other groups including neuropathic pain patients.  Multivariate analysis revealed partially overlapping and partially distinct CSF profiles in neuropathic pain patients compared with fibromyalgia and controls for several other proteins including angiotensinogen (AGT), prostaglandin-H2 D-isomerase (PTGDS), neurexin-1 (NRXN1), superoxide dismutase 1 (SOD1) and superoxide dismutase 3 (SOD3).

Conclusions: Our results, suggest that the CSF protein profiles of neuropathic pain and fibromyalgia patients may be different from each other and from those of controls. CSF levels of APOC1, ENPP2, AGT, PTGDS, NRXN1, SOD1 and SOD3 should be further investigated for their potential to serve as biomarkers of different kinds of pain pathophysiology.

Nyckelord [en]
cerebrospinal fluid, biomarker, human, chronic pain, neuropathic pain, fibromyalgia, spinal cord stimulation, mechanism of action, radiculopathy, protein, inflammation, neuroinflammation, mass spectrometry, antibody suspension bead array, protein profiling
Nationell ämneskategori
Neurovetenskaper Klinisk laboratoriemedicin Hälsovetenskaper Anestesi och intensivvård Biomedicinsk laboratorievetenskap/teknologi
Forskningsämne
Anestesiologi och intensivvård; Bioinformatik; Biokemi; Biologi med inriktning mot molekylärbiologi; Biomedicinsk laboratorievetenskap; Kemi med inriktning mot analytisk kemi; Klinisk kemi; Medicinsk vetenskap; Molekylär medicin
Identifikatorer
URN: urn:nbn:se:uu:diva-326158OAI: oai:DiVA.org:uu-326158DiVA, id: diva2:1119183
Projekt
Berzelii Technology Centre of Neurodiagnostics
Forskningsfinansiär
AFA Försäkring, 140341VINNOVAVetenskapsrådetTillgänglig från: 2017-07-03 Skapad: 2017-07-03 Senast uppdaterad: 2018-01-13
Ingår i avhandling
1. Biomarkers for Better Understanding of the Pathophysiology and Treatment of Chronic Pain: Investigations of Human Biofluids
Öppna denna publikation i ny flik eller fönster >>Biomarkers for Better Understanding of the Pathophysiology and Treatment of Chronic Pain: Investigations of Human Biofluids
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Chronic pain affects 20 % of the global population, causes suffering, is difficult to treat, and constitutes a large economic burden for society. So far, the characterization of molecular mechanisms of chronic pain-like behaviors in animal models has not translated into effective treatments.

In this thesis, consisting of five studies, pain patient biofluids were analyzed with modern proteomic methods to identify biomarker candidates that can be used to improve our understanding of the pathophysiology chronic pain and lead to more effective treatments.

Paper I is a proof of concept study, where a multiplex solid phase-proximity ligation assay (SP-PLA) was applied to cerebrospinal fluid (CSF) for the first time. CSF reference protein levels and four biomarker candidates for ALS were presented. The investigated proteins were not altered by spinal cord stimulation (SCS) treatment for neuropathic pain. In Paper II, patient CSF was explored by dimethyl and label-free mass spectrometric (MS) proteomic methods. Twelve proteins, known for their roles in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity, were identified to be associated with SCS treatment of neuropathic pain. In Paper III, proximity extension assay (PEA) was used to analyze levels of 92 proteins in serum from patients one year after painful disc herniation. Patients with residual pain had significantly higher serum levels of 41 inflammatory proteins. In Paper IV, levels of 55 proteins were analyzed by a 100-plex antibody suspension bead array (ASBA) in CSF samples from two neuropathic pain patient cohorts, one cohort of fibromyalgia patients and two control cohorts. CSF protein profiles consisting of levels of apolipoprotein C1, ectonucleotide pyrophosphatase/phosphodiesterase family member 2, angiotensinogen, prostaglandin-H2 D-isomerase, neurexin-1, superoxide dismutases 1 and 3 were found to be associated with neuropathic pain and fibromyalgia. In Paper V, higher CSF levels of five chemokines and LAPTGF-beta-1were detected in two patient cohorts with neuropathic pain compared with healthy controls.

In conclusion, we demonstrate that combining MS proteomic and multiplex antibody-based methods for analysis of patient biofluid samples is a viable approach for discovery of biomarker candidates for the pathophysiology and treatment of chronic pain. Several biomarker candidates possibly reflecting systemic inflammation, lipid metabolism, and neuroinflammation in different pain conditions were identified for further investigation.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 89
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1342
Nyckelord
chronic pain, neuropathic pain, lumbar radicular pain, amyotrophic lateral sclerosis, radiculopathy, fibromyalgia, pathophysiology, spinal cord stimulation, mechanism of action, disc herniation, cerebrospinal fluid, plasma, biomarker, human, protein, chemokines, cytokines, inflammation, neuroinflammation, mass spectrometry, proximity ligation assay, proximity extension assay, antibody suspension bead array, protein profiling, molecular medicine, personalized medicine
Nationell ämneskategori
Anestesi och intensivvård Klinisk laboratoriemedicin Biomedicinsk laboratorievetenskap/teknologi Analytisk kemi
Forskningsämne
Anestesiologi och intensivvård; Biomedicinsk laboratorievetenskap; Kemi med inriktning mot analytisk kemi; Medicinsk vetenskap; Molekylär medicin
Identifikatorer
urn:nbn:se:uu:diva-326180 (URN)978-91-513-0006-1 (ISBN)
Disputation
2017-09-15, Enghoffsalen, Ingång 50, bv, Akademiska sjukhuset, Uppsala, 09:00 (Svenska)
Opponent
Handledare
Projekt
Uppsala Berzelii Technology Centre for Neurodiagnostics
Forskningsfinansiär
VetenskapsrådetVINNOVA
Tillgänglig från: 2017-08-24 Skapad: 2017-07-03 Senast uppdaterad: 2017-09-08

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