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Physiological metabolic differences between Ncf1 mutant and wild type mice
Umeå University, Faculty of Science and Technology, Department of Chemistry.
MediCity Research Laboratory, University of Turku, Turku, Finland. (Turku Graduate School of Biomedical Sciences (TuBS), Turku, Finland)
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The Ncf1 gene is a major determinant of disease severity in experimental animal models of Rheumatoid Arthritis. The Ncf1 codes a protein that is important for regulating the activity of the NADPH oxidase (NOX2) complex. This complex produces reactive oxygen species (ROS) important both for killing off pathogens but also for regulating the immune response.Using metabolic profiling techniques we have found that mutation of the Ncf1 gene leads to alteration of the metabolic profile even without induction of inflammation, thus demonstrating a physiological role for the gene. Transgenic expression of Ncf1 in macrophages restored the metabolic profile so it was very similar to that seen in wild type animals. This indicates that macrophages have an immune regulatory role even outside inflammation.The metabolic differences between genotypes were subtle so the experiments were repeated to ensure validity of the results. The most stable metabolic effect across studies was an increase in free fatty acids in animals with functional NOX2 oxidation. This is likely due to production of immune regulatory compounds in the pathways initiated by phospholipase A2.

National Category
Natural Sciences
Research subject
biological chemistry
Identifiers
URN: urn:nbn:se:umu:diva-59476OAI: oai:DiVA.org:umu-59476DiVA: diva2:552457
Available from: 2012-09-14 Created: 2012-09-14 Last updated: 2012-09-14Bibliographically approved
In thesis
1. Metabolic variation in autoimmune diseases
Open this publication in new window or tab >>Metabolic variation in autoimmune diseases
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Metabolisk variation i autoimmuna sjukdomar
Abstract [en]

The human being and other animals contain immensely complex biochemical processes that govern their function on a cellular level. It is estimated that several thousand small molecules (metabolites) are produced by various biochemical pathways in humans. Pathological processes can introduce perturbations in these biochemical pathways which can lead to changes in the amounts of some metabolites.Developments in analytical chemistry have made it possible measure a large number metabolites in a single blood sample, which gives a metabolic profile. In this thesis I have worked on establishing and understanding metabolic profiles from patients with rheumatoid arthritis (RA) and from animal models of the autoimmune diseases diabetes mellitus type 1 (T1D) and RA.Using multivariate statistical methods it is possible to identify differences between metabolic profiles of different groups. As an example we identified differences between patients with RA and healthy volunteers. This can be used to elucidate the biochemical processes that are active in a given pathological condition.Metabolite concentrations are affected by a many other things than the presence or absence of a disease. Both genomic and environmental factors are known to influence metabolic profiles. A main focus of my work has therefore been on finding strategies for ensuring that the results obtained when comparing metabolic profiles were valid and relevant. This strategy has included repetition of experiments and repeated measurement of individuals’ metabolic profiles in order to understand the sources of variation.Finding the most stable and reproducible metabolic effects has allowed us to better understand the biochemical processes seen in the metabolic profiles. This makes it possible to relate the metabolic profile differences to pathological processes and to genes and proteins involved in these.The hope is that metabolic profiling in the future can be an important tool for finding biomarkers useful for disease diagnosis, for identifying new targets for drug design and for mapping functional changes of genomic mutations. This has the potential to revolutionize our understanding of disease pathology and thus improving health care.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. 47 p.
Keyword
Rheumatoid Arthritis, Diabetes Mellitus type 1, Metabolic Profiling, Metabolomics, Chemometrics, Multivariate Data Analysis, Mass Spectrometry
National Category
Natural Sciences
Research subject
biological chemistry
Identifiers
urn:nbn:se:umu:diva-59475 (URN)978-91-7459-480-5 (ISBN)
Public defence
2012-10-05, KBC-huset, Lilla hörsalen (KB3A9), Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2012-09-14 Created: 2012-09-14 Last updated: 2012-09-14Bibliographically approved

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