Mechanisms of TRAFSignaling

This thesis describes the investigation of the mechanisms of signal transduction activated by tumor necrosis factor (TNF) superfamily proteins. Ligands of the TNF family engage TNF receptor (TNFR) family proteins, leading to a wide variety of cellular effects, these interactions are implicated in inflammation, immune regulation, bone homeostasis, and development. TNFR proteins lack intrinsic enzymatic activity, and are coupled to intracellular signaling cascades by TNFR associated factor (TRAF) proteins, which are cytoplasmic adaptor molecules. The roles of TRAF1, TRAF2, and TRAF6 are investigated structurally and functionally in the activation of NF-kB, AP-1, and Src-family kinases. Cbl proteins are identified as positive and negative regulators of Src-family kinase signaling. The molecular structure of TRAF6 is determined and structure-function relationships between TRAF6 and the receptors to which it binds are examined. A physiological role for TRAF1 is identified in the regulation of TRAF2. This finding elucidates the role of translocation into lipid rafts in TRAF signaling regulation. The implications of these findings are considered primarily in the reciprocal regulation of immunity and bone homeostasis by TRAF-mediated signaling pathways

Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma

Severe asthma represents a major unmet clinical need. Eosinophilic inflammation persists in the airways of many patients with uncontrolled asthma, despite high-dose inhaled corticosteroid therapy. Suppressors of cytokine signalling (SOCS) are a family of molecules involved in the regulation of cytokine signalling via inhibition of the Janus kinase–signal transducers and activators of transcription pathway. We examined SOCS expression in the airways of asthma patients and investigated whether this is associated with persistent eosinophilia.Healthy controls, mild/moderate asthmatics and severe asthmatics were studied. Whole genome expression profiling, quantitative PCR and immunohistochemical analysis were used to examine expression of SOCS1, SOCS2 and SOCS3 in bronchial biopsies. Bronchial epithelial cells were utilised to examine the role of SOCS1 in regulating interleukin (IL)-13 signalling in vitro.SOCS1 gene expression was significantly lower in the airways of severe asthmatics compared with mild/moderate asthmatics, and was inversely associated with airway eosinophilia and other measures of T-helper type 2 (Th2) inflammation. Immunohistochemistry demonstrated SOCS1 was predominantly localised to the bronchial epithelium. SOCS1 overexpression inhibited IL-13-mediated chemokine ligand (CCL) 26 (eotaxin-3) mRNA expression in bronchial epithelial cells.Severe asthma patients with persistent airway eosinophilia and Th2 inflammation have reduced airway epithelial SOCS1 expression. SOCS1 inhibits epithelial IL-13 signalling, supporting its key role in regulating Th2-driven eosinophilia in severe asthma.</jats:p

Increased autophagy-related 5 gene expression is associated with collagen expression in the airways of refractory asthmatics

Background: Fibrosis, particularly excessive collagen deposition, presents a challenge for treating asthmatic individuals. At present, no drugs can remove or reduce excessive collagen in asthmatic airways. Hence, the identification of pathways involved in collagen deposition would help to generate therapeutic targets to interfere with the airway remodeling process. Autophagy, a cellular degradation process, has been shown to be dysregulated in various fibrotic diseases, and genetic association studies in independent human populations have identified autophagy-related 5 (ATG5) to be associated with asthma pathogenesis. Hence, the dysregulation of autophagy may contribute to fibrosis in asthmatic airways. Objective: This study aimed to determine if (1) collagen deposition in asthmatic airways is associated with ATG5 expression and (2) ATG5 protein expression is associated with asthma per se and severity. Methods: Gene expression of transforming growth factor beta 1, various asthma-related collagen types [collagen, type I, alpha 1; collagen, type II, alpha 1; collagen, type III, alpha 1; collagen, type V, alpha 1 (COL5A1) and collagen, type V, alpha 2], and ATG5 were measured using mRNA isolated from bronchial biopsies of refractory asthmatic subjects and assessed for pairwise associations. Protein expression of ATG5 in the airways was measured and associations were assessed for asthma per se, severity, and lung function. Main results: In refractory asthmatic individuals, gene expression of ATG5 was positively associated with COL5A1 in the airways. No association was detected between ATG5 protein expression and asthma per se, severity, and lung function. Conclusion and clinical relevance: Positive correlation between the gene expression patterns of ATG5 and COL5A1 suggests that dysregulated autophagy may contribute to subepithelial fibrosis in the airways of refractory asthmatic individuals. This finding highlights the therapeutic potential of ATG5 in ameliorating airway remodeling in the difficult-to-treat refractory asthmatic individuals

STYLE AS EXEMPLIFICATIONAL ASPECT OF DISCOURSE

Goodmanova semiotika i teorija stila znatno utječu na suvremena promišljanja pojma stil i određivanja nadležnosti literarne stilistike, naročito u Francuskoj. Ključnim se u tome kontekstu pokazuje Goodmanov koncept egzemplifikacije kao specifične referencijalne funkcije. U ovome radu donosi se kritički pregled Goodmanovih teza i njegovih nastavljača, posebice G. Genettea.Goodman\u27s semiotics and the theory of style are highly influental in contemporary conteptualizations of style and in defining the scope of literary stylistics, particulary in France. The key concept in that context is exemplification – a specific referential function. This paper presents a critical summary of Nelson Goodman\u27s hypotheses as well as his successors\u27, namely Gérard Genette