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Array-based identification of disease-associated proteins
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-6560-6124
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

To increase our understanding of the human body in both health and disease, proteins can be studied in samples such as plasma and serum to provide a molecular profile of the physiological status. In the work presented in this thesis, array-based methods were used to study associations of protein and autoantibody profiles with disease. The methods included antibody suspension bead arrays for protein profiling and planar antigen arrays or antigen suspension bead arrays for autoantibody profiling.

In Paper I, we studied protein levels in the context of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We identified three proteins, NEFM, RGS18 and SLC25A20, to be significantly elevated in patients with ALS. We also evaluated the diagnostic potential of these proteins, reaching areas under the curves (AUCs) between 0.78 and 0.86 for each of the three proteins individually.

In Paper II, drug-induced liver injury (DILI) cases and controls were studied in four independent cohorts of longitudinal and cross-sectional design and covering a range of drugs. The protein FABP1 was elevated in DILI cases upon initiation of treatment whereas CDH5 were elevated before treatment. Furthermore, we compared FABP1 with the clinically measured alanine aminotransferase (ALT), and identified some aspects in which FABP1 was superior: tissue distribution – FABP1 was not found in skeletal and heart muscle tissue, injuries in which can cause elevations of ALT; kinetics – FABP1 is smaller and has a lower half-life compared to ALT. Both of these circumstances mean that FABP1 as a biomarker has the potential to more accurately reflect ongoing injury.

In Paper III, asthma of different severities, chronic obstructive pulmonary disease and healthy controls from two independent cohorts were studied. The levels of ten proteins were verified to be significantly elevated in severe asthma compared to both mild-to-moderate asthma and healthy controls in both cohorts. We also clustered asthma patients based on their protein profiles and identified six subgroups that could help to guide the appropriate treatment.

In Paper IV, atopic dermatitis (AD) of different severities and healthy controls were studied. Increased autoantibody reactivity to four antigens, KRTAP17-1, HSPA4, S100A12 and S100Z, were observed in AD patients or in any of the two severity disease subgroups compared to controls.

In summary, the work included in this thesis highlights the applicability of protein array-based methods in various contexts and in studying various research questions. Disease-associated proteins were identified and further studies will determine their utility.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2018. , p. 69
Series
TRITA-CBH-FOU ; 2018:28
Keywords [en]
Affinity proteomics, Antibody array, Antigen array, Amyotrophic lateral sclerosis, Asthma, Atopic dermatitis, Biomarker discovery, Drug-induced liver injury, Microarray, Plasma, Protein microarray, Protein profiling, Serum, Suspension bead array
National Category
Medical Biotechnology
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-233541ISBN: 978-91-7729-902-8 (print)OAI: oai:DiVA.org:kth-233541DiVA, id: diva2:1241342
Public defence
2018-09-14, Air & Fire, SciLifeLab, Tomtebodavägen 23A, Solna, 10:00 (English)
Opponent
Supervisors
Note

QC 20180823

Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2018-08-23Bibliographically approved
List of papers
1. Plasma profiling revelas three proteins associated to amyotrophic lateral sclerosis
Open this publication in new window or tab >>Plasma profiling revelas three proteins associated to amyotrophic lateral sclerosis
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2014 (English)In: Annals of Clinical and Translational Neurology, ISSN 2328-9503, Vol. 1, no 8, p. 544-553Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease leading to muscular paralysis and death within 3-5 years from onset. Currently, there are no reliable and sensitive markers able to substantially shorten the diagnosis delay. The objective of the study was to analyze a large number of proteins in plasma from patients with various clinical phenotypes of ALS in search for novel proteins or protein profiles that could serve as potential indicators of disease.

METHODS: Affinity proteomics in the form of antibody suspension bead arrays were applied to profile plasma samples from 367 ALS patients and 101 controls. The plasma protein content was directly labeled and protein profiles obtained using 352 antibodies from the Human Protein Atlas targeting 278 proteins. A focused bead array was then built to further profile eight selected protein targets in all available samples.

RESULTS: Disease-associated significant differences were observed and replicated for profiles from antibodies targeting the proteins: neurofilament medium polypeptide (NEFM), solute carrier family 25 (SLC25A20), and regulator of G-protein signaling 18 (RGS18).

INTERPRETATION: Upon further validation in several independent cohorts with inclusion of a broad range of other neurological disorders as controls, the alterations of these three protein profiles in plasma could potentially provide new molecular markers of disease that contribute to the quest of understanding ALS pathology.

National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:kth:diva-158941 (URN)10.1002/acn3.83 (DOI)000209815300003 ()25356426 (PubMedID)2-s2.0-84929577531 (Scopus ID)
Note

QC 20150115

Available from: 2015-01-15 Created: 2015-01-15 Last updated: 2020-03-10Bibliographically approved
2. Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury
Open this publication in new window or tab >>Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury
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2016 (English)In: Liver international (Print), ISSN 1478-3223, E-ISSN 1478-3231, Vol. 37, no 1, p. 132-140Article in journal (Refereed) Published
Abstract [en]

Background & Aims: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. Methods: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. Results: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. Conclusions: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers. © 2016 John Wiley & Sons A/S.

Place, publisher, year, edition, pages
John Wiley & Sons, 2016
Keywords
Affinity proteomics, Biomarker discovery, Drug-induced liver injury, Plasma profiling, Suspension bead arrays
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-194625 (URN)10.1111/liv.13174 (DOI)000393769900014 ()27224670 (PubMedID)2-s2.0-84977547750 (Scopus ID)
Note

Correspondence Address: Schuppe-Koistinen, I.email: ina.schuppe-koistinen@scilifelab.se. QC 20161101

Available from: 2016-11-01 Created: 2016-10-31 Last updated: 2020-03-09Bibliographically approved
3. Identification of proteins associated with asthma severity
Open this publication in new window or tab >>Identification of proteins associated with asthma severity
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Biotechnology
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-233540 (URN)
Note

QC 20180823

Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2018-08-23Bibliographically approved
4. The antimicrobial protein S100A12 identified as a potential autoantigen in a subgroup of atopic dermatitis patients
Open this publication in new window or tab >>The antimicrobial protein S100A12 identified as a potential autoantigen in a subgroup of atopic dermatitis patients
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Biotechnology
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-233539 (URN)
Note

QC 20180823

Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2018-08-23Bibliographically approved

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