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Novel pancreatic beta cell-specific proteins: Antibody-based proteomics for identification of new biomarker candidates
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
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2012 (English)In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 75, no 9, 2611-2620 p.Article in journal (Refereed) Published
Abstract [en]

Beta cell-specific surface targets are required for non-invasive monitoring of beta cell mass, which could be used for evaluation of new diabetes treatments as well as to help unravel pathogenic mechanisms underlying beta cell dysfunction. By antibody-based proteomics, we have identified and explored a set of islet cell-specific proteins. A search algorithm in the Human Protein Atlas was set up for identification of islet-specific proteins that yielded 27 hits, of which twelve showed a clear membranous expression pattern or had predicted transmembrane regions. The specificity of the identified proteins was investigated by immunohistochemical staining of pancreas sections from diabetic and non-diabetic subjects. No expression of these antigens could be detected in the exocrine pancreas. Colocalization with insulin and glucagon was further determined by confocal microscopy using isolated human islets. All antibodies specifically stained human islets and colocalization analysis revealed that four proteins were exclusively expressed in beta cells. Importantly, these antibodies were negative in sections from subjects with long-standing type 1 diabetes. In the present study, we present four proteins; DGCR2, GBF1, GPR44 and SerpinB10, the expression of which has not previously been described in beta cells.

Place, publisher, year, edition, pages
2012. Vol. 75, no 9, 2611-2620 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-175948DOI: 10.1016/j.jprot.2012.03.008ISI: 000304634000009PubMedID: 22465717OAI: oai:DiVA.org:uu-175948DiVA: diva2:533643
Available from: 2012-06-14 Created: 2012-06-14 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Tissue Microarrays for Analysis of Expression Patterns
Open this publication in new window or tab >>Tissue Microarrays for Analysis of Expression Patterns
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins are essential building blocks in every living cell, and since the complete human genome was sequenced in 2004, researchers have attempted to map the human proteome, which is the functional representation of the genome. One such initiative is the Human Protein Atlas programme (HPA), which generates monospecific antibodies towards all human proteins and uses these for high-throughput tissue profiling on tissue microarrays (TMAs). The results are publically available at the website www.proteinatlas.org.

In this thesis, TMAs were used for analysis of expression patterns in various research areas. Different search queries in the HPA were tested and evaluated, and a number of potential biomarkers were identified, e.g. proteins exclusively expressed in islets of Langerhans, but not in exocrine glandular cells or other abdominal organs close to pancreas. The identified candidates were further analyzed on TMAs with pancreatic tissues from normal and diabetic individuals, and colocalization studies with insulin and glucagon revealed that several of the investigated proteins (DGCR2, GBF1, GPR44 and SerpinB10) appeared to be beta cell specific. Moreover, a set of proteins differentially expressed in lung cancer stroma was further analyzed on a clinical lung cancer cohort in the TMA format, and one protein (CD99) was significantly associated with survival. In addition, TMAs with tissue samples from different species were generated, e.g. for mapping of influenza virus attachment in various human and avian tissues. The results showed that the gull influenza virus H16N3 attached to human respiratory tract and eye, suggesting possible transmission of the virus between gull and human. TMAs were also used for analysis of protein expression differences between humans and other primates, and two proteins (TCF3 and SATB2) proved to be significantly differentially expressed on the human lineage at both the protein level and the RNA level.  

In conclusion, this thesis exemplifies the potential of the TMA technology, which can be used for analysis of expression patterns in a large variety of research fields, such as biomarker discovery, influenza virus research or further understanding of human evolution.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 846
Keyword
Tissue microarrays, Antibody-based proteomics, Immunohistochemistry, Biomarker discovery, Diabetes, Lung cancer, Influenza virus, Evolution
National Category
Endocrinology and Diabetes Infectious Medicine Cancer and Oncology Medical Genetics
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-186272 (URN)978-91-554-8551-1 (ISBN)
Public defence
2013-01-25, Rudbeck hall, Rudbeck laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Available from: 2012-12-21 Created: 2012-11-28 Last updated: 2013-02-11Bibliographically approved

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Lindskog, CeciliaKorsgren, OllePontén, FredrikEriksson, Jan WJohansson, LarsDanielsson, Angelika

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