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Categoria:  events
Inizio:  venerdì 5 maggio 2017 - Fine:  venerdì 5 maggio 2017
Titolo:  2017 IBP-CNR Seminar Series: "Inflammatory response in Cystic Fibrosis lungs: in search of druggable targets"
Dettagli:  

Institute of Protein Biochemistry, CNR.

Via P. Castellino, 111 - 80131 Napoli

2017 IBP Seminar Series

CNR Conference Hall

Friday, May 5th, 2017 at 15:00

 

Prof. Giulio Cabrini

Department of Pathology and Diagnostics, University Hospital of Verona, Italy

"Inflammatory response in Cystic Fibrosis lungs: in search of druggable targets"

Host: Dr. Alberto Luini

Tel. 081-6132722; e-mail: a.luini@ibp.cnr.it

Changes in intracellular Ca2+ concentration are key regulators of the activities of ion transporters and channels involved in transepithelial ion transport and fluid secretion in airway epithelia (reviewed in 1). This includes Ca2+-regulated Cl- channels that could interplay with or compensate for defective CFTR-mediated ion transport. Interestingly, intracellular Ca2+ signals consequent to activation of apical G-protein-coupled-receptors are increased in CF airway epithelia. Although the molecular mechanism of this increase is puzzling, abnormal Ca2+ influx has been directly linked to F508del CFTR pathobiology (reviewed in 2). In addition, expansion of the endoplasmic reticulum (ER) Ca2+ stores has been demonstrated in CF primary airway epithelial cells exposed to chronic bacterial infection, as a result of an Unfolded Protein Response, a form of inflammation-dependent ER stress (reviewed in 3). Thus, dysregulated intracellular Ca2+ homeostasis in CF bronchial epithelial cells has been claimed by different viewpoints as a potential druggable target to compensate for CFTR Cl- transport defect and/or to reduce excessive CF lung inflammation. However, the precise identification of the Ca2+ transporter/channel to be targeted is contradictory and requires further understanding on the pros and cons of pharmacological modulation of intracellular Ca2+ mobilization. Results focusing on the role of some of the intracellular Ca2+ modulators activated upon interaction of P.aeruginosa with bronchial epithelial cells, inducing the classical intracellular pro-inflammatory signaling leading to upregulation of IL-8, IL-1b, IL-6 and TNF-a release will be presented. We previously showed that direct interaction of P.aeruginosa with Toll-like Receptors (TLR2, 5 and 4) strongly overexpresses IL-8 gene by MyD88/dependent phosphorylation of Mitogen Activated Protein kinases ERK1/2, p38, JNK, and downstream kinases RSK1/2 and HSP27, leading to intranuclear translocation of transcription factors such as NF-kB, NF-IL6, AP-1, CREB and CHOP (4). Release of ATP in the extracellular milieu is able to sustain a P2Y purinergic receptors- and phospolipase C beta 3-dependent release of intracellular Ca2+ which potentiates the MyD88-dependent inflammatory pathways (5). More recently, we observed that flagellin from P.aeruginosa alters in a CF-specific manner the Ca2+ homeostasis, leading to mitochondrial perturbation with increased Ca2+ influx and production of Reactive Oxygen Species, which drives to exaggerated inflammasome activation and the release of IL-1b (6). Investigation on the intracellular Ca2+ refill systems lead to propose the TRPA1 as potentially druggable channels (7). This opens further questions on the role of the different intracellular Ca2+ compartments and subcellular domains, widening the panel of candidate molecular targets to be considered.

 

Drs. Maria Rosaria Coscia & Stefania Mariggiò
Seminar Coordinators
Institute of Protein Biochemistry, CNR
Via P. Castellino, 111
80131 Naples Italy
Tel 0039 081 6132556/545

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