Spelling suggestions: "subject:"inflammatory signaling"" "subject:"nflammatory signaling""
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Harnessing Inflammatory Signaling to Promote Bone Regeneration and Mitigate Joint DamageMountziaris, Paschalia Maria January 2012 (has links)
Inflammatory processes are infamous for their destructive effects on tissues and joints in a variety of diseases. Within the body, inflammation is a highly regulated biological response whose purpose is to promote tissue regeneration following injury. However, in certain settings, inflammation persists and leads to progressive tissue destruction. This thesis focused on modulating inflammatory signaling in both contexts. Part I investigated the effects of a model pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α), on the in vitro osteogenic differentiation of mesenchymal stem cells (MSCs). In contrast, Part II describes the development and in vivo evaluation of the first intra-articular controlled release system for the temporomandibular joint (TMJ), which silences inflammatory signaling and thus mitigates the painful joint damage seen in inflammatory TMJ disease. The following specific aims were addressed: (1) to determine the concentration of TNF-α that enhances in vitro osteogenic differentiation of MSCs; (2) to determine the temporal pattern of TNF-α delivery that enhances in vitro osteogenic differentiation of MSCs; (3) to determine the impact of bone-like extracellular matrix (ECM) on the concentration and temporal pattern of TNF-α delivery that enhances in vitro osteogenic differentiation of MSCs; (4) to evaluate the biocompatibility of intra-articular microparticles in the rat TMJ; (5) to develop a microparticle-based formulation for sustained release of a model anti-inflammatory small interfering ribonucleic acid (siRNA); and (6) to evaluate the therapeutic efficacy of intra-articular microparticles delivering siRNA in an animal model of TMJ inflammation. These studies led to the development of powerful strategies to rationally control inflammation to promote bone regeneration and mitigate joint damage in the setting of disease, both of which will ultimately improve the quality and specificity of therapies available in modern medicine. / Only volume 2 has been digitized.
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Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signalingRutherford, C., Speirs, C., Williams, Jamie J.L., Ewart, M-A., Mancini, S.J., Hawley, S.A., Delles, C., Viollet, B., Costa-Pereira, A.P., Baillie, G.S., Salt, I.P., Palmer, Timothy M. 2016 October 1921 (has links)
Yes / AMP-activated protein kinase (AMPK) is a pivotal regulator of metabolism at the
cellular and organismal levels. AMPK also suppresses inflammation. We found that pharmacological
activation of AMPK rapidly inhibited the Janus kinase (JAK)–signal transducer and activator of
transcription (STAT) pathway in various cells. In vitro kinase assays revealed that AMPK directly
phosphorylated two residues (Ser515 and Ser518) within the SH2 domain of JAK1. Activation of
AMPK enhanced the interaction between JAK1 and 14-3-3 proteins in cultured vascular endothelial
cells and fibroblasts, an effect which required the presence of Ser515 and Ser518 and was abolished
in cells lacking AMPK catalytic subunits. Mutation of Ser515 and Ser518 abolished AMPKmediated
inhibition of JAK-STAT signaling stimulated either by the sIL-6Rα/IL-6 complex or
by expression of a constitutively active V658F-mutant JAK1 in human fibrosarcoma cells.
Clinically used AMPK activators metformin and salicylate enhanced the inhibitory
phosphorylation of endogenous JAK1 and inhibited STAT3 phosphorylation in primary vascular
endothelial cells. Therefore our findings reveal a mechanism by which JAK1 function and
inflammatory signaling may be suppressed in response to metabolic stress and provide a
mechanistic rationale for the investigation of AMPK activators in a range of diseases associated with enhanced activation of the JAK-STAT pathway.
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