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Proteomics as a multifaceted tool in medicine and environmental assessment
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteomics is evolving as a multi-faceted tool for addressing various biochemical and biomedical queries in the field of scientific research. This involves various stages, ranging from sample preparation to data analysis and biological interpretation. Sample preparation involves isolating proteins from the sample source, purifying and digesting them to initiate shotgun proteomics. Shotgun proteomics identifies proteins by bottom-up proteomic approaches where proteins are identified from the fragmentation spectra of their own peptides.

Paper I: deals with the simplification of functional characterization for nanoparticles intended for use in biomedicine. Proteomics was constructive in differentiating and semi-quantifying the surface of protein corona. This could be beneficial in predicting the interactions between nanoparticles and a biological entity like the cell or a receptor protein and provide initial valuable information related to targeting, uptake and safety.

Paper II: deals with understanding effects of TiO2 nanoparticles on endothelial cells. A combinatorial approach, involving transcriptomics and proteomics was used to identify aberrations in the permeability and integrity of endothelial cells and tissues. Our study also investigated the correlation of size and how they motivated a differential cellular response. In case of intravenous entry for nanoparticles in targeted drug delivery systems, endothelial cells are the first barrier encountered by these drug carriers. This evaluation involving endothelial cell response could be very instrumental during the designing of NP based drug delivery systems.

Paper III: Pharmaceuticals and its metabolites could be very hazardous, especially if its disposal is not managed properly. Since water bodies are the ultimate sink, these chemicals could end up there, culminating in toxicity and other ‘mixture effects’ in combination with other factors. To evaluate the effects of the pharmaceutical, propranolol and climatic factors like low salinity conditions, a microcosm exposure was designed and shotgun proteomics helped understand its impact on mussel gills. In this study too, a combination of transcriptomics and proteomics unveiled molecular mechanisms altered in response to stressors, both individually and in combination.

Paper IV: An interplay of various factors like EBF1 and PAX5 determines B-cell lineage and commitment. This might have been materialized by direct and transient proteinprotein interactions. A unique method called BioID helped screen relevant interactions in living cells by the application of a promiscuous biotin ligase enzyme capable of tagging proteins through biotinylation based on a proximity radius. Biotinylation of endogenous proteins enabled their selective isolation by exploiting the high affinity of biotin and streptavidin on streptavidin coated agarose beads, leading to their identification by mass spectrometry. The biotinylated proteins were potential candidate interactors of EBF1 and PAX5, which were later confirmed by sequencing techniques like ChIP-Seq, ATAC seq, and visualization techniques like proximity ligation assay (PLA).

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. , 67 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1585
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Biochemistry and Molecular Biology Bioinformatics and Systems Biology Cell and Molecular Biology Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-139867ISBN: 978-91-7685-458-7 (print)OAI: oai:DiVA.org:liu-139867DiVA: diva2:1134190
Public defence
2017-09-08, Hasselquist, Campus US, Linköping, 09:30 (English)
Opponent
Supervisors
Available from: 2017-08-18 Created: 2017-08-18 Last updated: 2017-08-18Bibliographically approved
List of papers
1. Surface proteomics on nanoparticles, a step to simplify the rapid prototyping of nanoparticles
Open this publication in new window or tab >>Surface proteomics on nanoparticles, a step to simplify the rapid prototyping of nanoparticles
2017 (English)In: Nanoscale Horizons, ISSN 2055-6756, no 1, 55-64 p.Article in journal (Refereed) Published
Abstract [en]

Engineered nanoparticles for biomedical applications requireincreasing effectiveness in targeting specific cells while preservingnon-target cell’s safety. We developed a surface proteomicsmethod for a rapid and systematic analysis of the interphasebetween the nanoparticle protein corona and the targeting cellsthat could implement the rapid prototyping of nanomedicines.Native nanoparticles entering in a protein-rich liquid mediaquickly form a macromolecular structure called protein corona.This protein structure defines the physical interaction betweennanoparticles and target cells. The surface proteins compose thefirst line of interaction between this macromolecular structureand the cell surface of a target cell. We demonstrated that SUSTU(SUrface proteomics, Safety, Targeting, Uptake) provides aqualitative and quantitative analysis from the protein coronasurface. With SUSTU, the spatial dynamics of the protein coronasurface can be studied. Data from SUSTU would ascertain thenanoparticle functionalized groups exposed at destiny that couldcircumvent preliminary in vitro experiments. Therefore thismethod could implement the analysis of nanoparticle targetingand uptake capability and could be integrated into a rapidprototyping strategy which is a major challenge in nanomaterialscience. Data are available via ProteomeXchange with identifierPXD004636.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
Keyword
nanoparticle, protein corona, mass spectrometry, surface proteomics, targeting, rapid prototyping, nanomedicine
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-132406 (URN)10.1039/c6nh00162a (DOI)
Projects
Nanoimpact; nanoparticles and rapid prototyping
Available from: 2016-11-09 Created: 2016-11-09 Last updated: 2017-08-18Bibliographically approved
2. Shotgun proteomics to unravel marine mussel (Mytilus edulis) response to long-term exposure to low salinity and propranolol in a Baltic Sea microcosm
Open this publication in new window or tab >>Shotgun proteomics to unravel marine mussel (Mytilus edulis) response to long-term exposure to low salinity and propranolol in a Baltic Sea microcosm
Show others...
2016 (English)In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 137, 97-106 p.Article in journal (Refereed) Published
Abstract [en]

Pharmaceuticals, among them the β-adrenoreceptor blocker propranolol, are an important group of environmental contaminants reported in European waters. Laboratory exposure to pharmaceuticals on marine species has been performed without considering the input of the ecosystem flow. To unravel the ecosystem response to long-term exposure to propranolol we have performed long-term exposure to propranolol and low salinity in microcosms. We applied shotgun proteomic analysis to gills of Mytilus edulis from those Baltic Sea microcosms and identified 2071 proteins with a proteogenomic strategy. The proteome profiling patterns from the 587 highly reproductive proteins among groups define salinity as a key factor in the mussel´s response to propranolol. Exposure at low salinity drives molecular mechanisms of adaptation based on a decrease in the abundance of several cytoskeletal proteins, signalling and intracellular membrane trafficking pathway combined with a response towards the maintenance of transcription and translation. The exposure to propranolol combined with low salinity modulates the expression of structural proteins including cilia functions and decrease the expression membrane protein transporters. This study reinforces the environment concerns of the impact of low salinity in combination with anthropogenic pollutants and anticipate critical physiological conditions for the survival of the blue mussel in the northern areas.

Place, publisher, year, edition, pages
Elsevier, 2016
Keyword
Mytilus edulis, shotgun proteomics, propranolol, low salinity, environmental monitoring, climate change
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-124213 (URN)10.1016/j.jprot.2016.01.010 (DOI)000374368800010 ()
Funder
Swedish Research Council
Note

Funding agencies: Swedish Research Council-Natural Science; VR-NT; Carl Trygger Foundation; Oscar and Lilli Lamms Minne Foundation; Angpanneforening Research Foundation; Magnus Bergsvall Foundation; IKERBASQUE; Basque Foundation for Science; VINNOVA; County Council of Oste

Available from: 2016-01-22 Created: 2016-01-22 Last updated: 2017-08-18Bibliographically approved

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