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Molecular Signatures of Neuropathic Pain: Revealing Pain-Related Signaling Processes in Spinal Cord Using Mass Spectrometric Methodologies
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, the detection of global proteomics alteration and changes in neuropeptide distribution caused by neuropathic pain in rat spinal cord tissue was the main focus. Neuropathic pain (NP) is a major clinical syndrome caused by disease or dysfunction of the nervous system and often mediated by neuronal networks in the spinal cord. The estimated prevalence of NP is 6-8% in general population. Only in the United States, the indirect cost associated with chronic pain has been estimated to 100 billion dollars each year and NP substantially contributes to this cost. So far, the underlying mechanisms of NP are not well understood. Proteomics techniques are commonly used in biology system studies, due to its high throughput, capability of unbiased analysis and sensitivity. It builds up a bridge to link genes, peptides, proteins, and the disease. Two proteomic/peptidomic approaches were developed, evaluated and discussed in this thesis. Both of them were further applied in the studies of neuropathic pain. First approach is a quantitative proteomic approach using liquid chromatography combined with Fourier transform mass spectrometry (LC-FTMS), which is developed for quantitative analysis of proteins originated from small central nervous system (CNS) samples. This approach was successfully applied in the study of the rat spinal cord tissue proteome in a neuropathic pain model. Another approach is using matrix assisted laser desorption ionization mass spectrometry (MALDI-MS) for the visualization of the distribution of neuropeptides in rat spinal cord, which in the future will be applied in investigating the ongoing signal transmission under neuropathic pain conditions. Results provided by these two methods are of high importance for the general understanding of the underlying pathophysiological mechanisms and potential identification of new targets for novel treatment of neuropathic pain.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1252
Keyword [en]
Mass spectrometry, Spinal cord, Neuropathic pain, Quantitative proteomics, Imaging mass spectrometry
National Category
Analytical Chemistry Neurosciences
Research subject
Chemistry with specialization in Analytical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-251334ISBN: 978-91-554-9244-1 (print)OAI: oai:DiVA.org:uu-251334DiVA: diva2:805488
Public defence
2015-06-05, B41, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2015-05-12 Created: 2015-04-15 Last updated: 2015-07-07
List of papers
1. Dimethyl-Labeling-Based Protein Quantification and Pathway Search: A Novel Method of Spinal Cord Analysis Applicable for Neurological Studies
Open this publication in new window or tab >>Dimethyl-Labeling-Based Protein Quantification and Pathway Search: A Novel Method of Spinal Cord Analysis Applicable for Neurological Studies
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2013 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, no 5, 2245-2252 p.Article in journal (Refereed) Published
Abstract [en]

In this paper we describe a simple, fast, and inexpensive approach for quantitative analysis of proteins originated from small central nervous system (CNS) samples, i.e., rat spinal cord. The presented sample preparation protocol and quantification results from isotope dimethyl labeling were statistically evaluated and approved as a reliable and robust method for animal model studies of neurological disorders. Combined with the biopathway analysis tool IPA, the method was applied for comparative analysis of proteins in the dorsal and ventral segments of the rat spinal cord. The results are in agreement with the previously published protein patterns in these tissues. A majority (73%) of proteins identified as “related with CNS development and functions” were found to be overexpressed in the dorsal section compared to the ventral segment. The pathway related to neuropathic pain was overrepresented in the dorsal tissue samples. The developed novel approach may be applied for analyses of the spinal cord mediated neurological dysfunctions and pathological pain.

National Category
Medical and Health Sciences
Research subject
Chemistry with specialization in Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-198456 (URN)10.1021/pr4001064 (DOI)000318589000022 ()
Available from: 2013-04-15 Created: 2013-04-15 Last updated: 2017-12-06Bibliographically approved
2. Proteomics of Neuropathic Pain: Proteins and Signaling Pathways Affected in a Rat Model
Open this publication in new window or tab >>Proteomics of Neuropathic Pain: Proteins and Signaling Pathways Affected in a Rat Model
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2014 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, no 9, 3957-3965 p.Article in journal (Refereed) Published
Abstract [en]

The myriad proteins may be involved in the mechanisms underlying the development and maintenance of neuropathic pain, an extremely disabling condition that originates from pathology of the nervous system. To address the mechanisms, we here analyzed proteins and cellular networks in the dorsal spinal cord mediating pain processing in a well-established rat model of neuropathic pain induced by spinal nerve ligation (SNL). Labeling-based proteomic methods together with high-resolution mass spectrometry for proteome analysis were applied. 38 proteins including synapsin 1 and microtubule-associated protein 2 were identified as differently expressed in the SNL group. Pathway analysis suggests that maladaptive changes in the levels of these proteins may contribute to abnormal synaptic transmission and neuronal intracellular signaling underlying the onset and development of neuropathic pain.

National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-232720 (URN)10.1021/pr500241q (DOI)000341345000009 ()24933149 (PubMedID)
Available from: 2014-09-23 Created: 2014-09-23 Last updated: 2017-12-05Bibliographically approved
3. Lateralized proteome response to the left and right side neuropathic pain in a rat model
Open this publication in new window or tab >>Lateralized proteome response to the left and right side neuropathic pain in a rat model
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(English)Manuscript (preprint) (Other academic)
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-251305 (URN)
Available from: 2015-04-15 Created: 2015-04-15 Last updated: 2015-05-12
4. Neuropeptide imaging in rat spinal cord with MALDI-TOF MS: Method evaluation for the application in pain related disease studies
Open this publication in new window or tab >>Neuropeptide imaging in rat spinal cord with MALDI-TOF MS: Method evaluation for the application in pain related disease studies
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(English)Manuscript (preprint) (Other academic)
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-251307 (URN)
Available from: 2015-04-15 Created: 2015-04-15 Last updated: 2015-05-12

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