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Antibody-based proteomics for discovery and exploration of proteins expressed in pancreatic islets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Ponten)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Ponten)
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2010 (English)In: Discovery Medicine, ISSN 1539-6509, E-ISSN 1944-7930, Vol. 9, no 49, 565-578 p.Article in journal (Refereed) Published
Abstract [en]

Abnormal glucose tolerance and deviant blood glucose levels are late stage clinical parameters that signify diabetes mellitus. To be able to diagnose the disease at an earlier stage and develop new tools for beta cell imaging, new molecular markers are needed. In the present study, five proteins highly expressed in pancreatic islets with no expression in the surrounding exocrine glandular cells of pancreas, and one protein with the opposite expression pattern, were identified by searches in the Human Protein Atlas (www.proteinatlas.org). The proteins were analyzed immunohistochemically on a specially designed tissue microarray, containing isolated human islets and pancreatic tissues with different characteristics, and compared to the expression of previously known markers of endocrine and exocrine pancreatic cells. Of the five novel endocrine markers, tetraspanin-7 was identified as a membrane-bound protein with exclusive positivity in islet cells. Also beta-2-microglobulin and ubiquitin carboxyl-terminal hydrolase isozyme L1 were expressed in a majority of islet cells, whereas sad1/unc-84 domain-containing protein 1 and beta-1,3-glucuronyltransferase 1 were positive in a smaller subset of islet cells. The potential exocrine marker galectin-2 was expressed in both exocrine acinary cells and pancreatic ductal cells, with no or low positivity in islet cells. In conclusion, antibody-based proteomics and specially designed tissue microarrays enable identification and exploration of novel proteins with differential expression in pancreatic islets. Here we describe 5 candidate proteins for further investigation of their physiological role and potential involvement in the pathogenesis of diabetes. One of these proteins, tetraspanin-7, is expressed on the cell membrane and could thus be a potential candidate for future development of tracers for beta cell imaging.

Place, publisher, year, edition, pages
2010. Vol. 9, no 49, 565-578 p.
National Category
Medical and Health Sciences
Research subject
Pathology
Identifiers
URN: urn:nbn:se:uu:diva-153099ISI: 000208638200011PubMedID: 20587347OAI: oai:DiVA.org:uu-153099DiVA: diva2:415174
Available from: 2011-05-05 Created: 2011-05-05 Last updated: 2017-12-11Bibliographically 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)
Opponent
Supervisors
Available from: 2012-12-21 Created: 2012-11-28 Last updated: 2013-02-11Bibliographically approved

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Lindskog, CeciliaAsplund, AnnaPontén, FredrikKorsgren, Olle

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