The role of the alarminHMGB1 in arthritis
ThenuclearproteinHigh mobility group box protein 1 (HMGB1) wasoriginallydiscoveredasthekeymediatorlinkingtissuedamagetoinflammation. HMGB1ispresentinallnucleatedcellsandisextraordinarilyconservedamongspecies,with rodentandhumanHMGB1being99% identical.HMGB1canbeeitherpassivelyreleasedfrom dyingcellsoractivelysecretedbystressedoractivatedcells.Whenreleasedfromcells,HMGB1inducesinflammationbyfirstrecruitinginflammatorycellsandthenbyactivatingthemtoreleaseproinflammatorymediators.
The ultimate aim of our research is to reveal how HMGB1 initiates and perpetuates inflammatory conditions and how its inflammatory activity is regulated. We have a specific focus on arthritis, as our earlier results demonstrate that HMGB1 is a mediator of cytokine production, cell migration and hyperalgesia during arthritis. Based on the knowledge obtained this far we consider HMGB1 to be a promising target molecule for anti-inflammatory and anti-rheumatic therapy and have developed new HMGB1-targeting interventions. We will accomplish our aims by undertaking clinical and ex vivo studies. We utilize our juvenile arthritis biobank to further understand the role of HMGB1 in arthritis pathogenesis and to demonstrate the potential value of HMGB1 as a diagnostic and/or prognostic biomarker. We also utilize experimental arthritis models to evaluate new HMGB1-specific therapy.
The project thus entails standard laboratory techniques such as ELISA, CBA and Luminex. The candidate should preferentially have skills in statistical analysis methods. Experience of experimental animal work is a merit.
Exploring mechanisms regulating the inflammatory activities of the alarminHMGB1
ThenuclearproteinHigh mobility group box protein 1 (HMGB1) wasoriginallydiscoveredasthekeymediatorlinkingtissuedamagetoinflammation. HMGB1ispresentinallnucleatedcellsandisextraordinarilyconservedamongspecies,with rodentandhumanHMGB1being99% identical.HMGB1canbeeitherpassivelyreleasedfrom dyingcellsoractivelysecretedbystressedoractivatedcells.Whenreleasedfromcells,HMGB1inducesinflammationbyfirstrecruitinginflammatorycellsandthenbyactivatingthemtoreleaseproinflammatorymediators.
We and others have demonstrated that the cytokine-inducing activity and the migration-inducing activity of HMGB1 is regulated by its cysteine redox status. HMGB1 is additionally known to interact with several receptors; mostly studied are the interactions with RAGE, leading to migration, and with TLR4, leading to cytokine production. More indepth studies are needed to further clarify the interplay of HMGB1 with HMGB1-binding receptors and its impact on both the magnitude as well as the specificity of the induced inflammatory response. We will expand receptor interaction studies to encompass TLR2 and TIM-3 in addition to TLR4 and RAGE and to study how post-translational modifications impact receptor interaction.
While mechanisms conveying the inflammatory activities of HMGB1 have been studied by many groups recently, less is known regarding the mechanisms downregulating HMGB1 activity. We will study proteases upregulated during inflammation and cancer, which are suggested to cleave HMGB1, and their impact on HMGB1 activity.
The project thus entails molecular biology techniques (transfection, production and purification of recombinant HMGB1), protein gels, Western blotting, ELISA and cell cultures (transfected cells and primary PBMC cultures). The candidate should preferentially have experience of these techniques.
PI: professor Helena Erlandsson Harris
Laboratory: The group belongs to the Rheumatology unit at KarolinskaInstitutet, Stockholm, Sweden. The laboratory is situated at the Center for Molecular Medicine, a research center with in KI with a focus on inflammatory diseases.
The group encompasses 10 persons; PhD students, post-docs, technicians and senior researchers.
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