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project info
Start date: 1 January 2016
End date: 31 December 2018
funding
Fund: European Regional Development Fund (ERDF)
Total budget: 181 500,00 €
EU contribution: 98 826,75 € (54,45%)
programme
Programming period: 2014-2020
Managing authority: Subdirección General de Gestión del FEDER, de la Dirección General de Fondos Europeos del Ministerio de Hacienda.
European Commission Topic

PHARMACOLOGICAL MODULATION OF INFLAMMATORY-REMODELED SIGNALISATION BY ISOFORM-SELECTIVE PDE4 INHIBITORS AND COMPARATORS IN RELEVANT IN VITRO HUMAN MODELS IN COPD

OBSTRUCTIVE CHRONIC PULMONARY DISEASE (COPD) INCREASES ITS MORBIDITY AND MORTALITY BY 2030, ACCORDING TO WHO THE 3 RD GLOBAL CAUSE OF MORTALITY, IMPOSING A SIGNIFICANT BURDEN ON THE HEALTH SYSTEM. MORE BASIC RESEARCH IS NEEDED ON THE MECHANISMS OF INFLAMMATION-REMODELING IN COPD AS NONE OF THE CURRENT PHARMACOLOGICAL TREATMENTS STOPS THE INEXORABLE PROGRESSION OF THE DISEASE. Phosphodiesterase-4 (PDE4) INHIBITORS REPRESENT A NEW CATEGORY OF ANTI-INFLAMATORS WITH roflumilast AS THE FIRST OF YOUR GROUP ADOPTED FOR THE TREATMENT OF EPOC._x000D_ OBJECTIVE: Pharmacological Analysis of Effects PRODUCED BY Selective INHIBITORS OF IMPLEMENTATION PDE4 COMPANY WITH STEROIES ON INFLAMATORY SYNALISATION VIASES IN HUMAN EXPERIMENTAL MODELS IN VITRO RELEVANTS FOR COPD._x000D_ FARMACOS: SELECTIVE ISOFORM INHIBITORS PDE4 VS. 2ND GENERACION ROFLUMILAST, IN CLINICAL USE; STEROIDS (DEXAMETHASONE, BUDESONIDE). REFERENCE PHARMACOS FOR HEURISTIC INTEREST (ANTIOXIDANTS, N-ACETYL-L-CYSTEINE) AND CLINIC (LONG-LASTING AGONISTS-2). CONCENTRATION TO BE USED IN RANGE PLASMA LEVELS. Use OF SIRNA FOR CANCELAR PDE4 ISOFORMAS will allow CONTRACTING RESULTS OF SELECTIVE INHIBITORS._x000D_ EXPERIMENT MODELS:_x000D_ 1) LEUCOCITO/ENDOTELY INTERATIONS. FLOW CHAMBER. VIDEOMICROSCOPY. CELLULAR ACTIVATION BY EXPOSURE TO TOBACCO SMOKE. DETERMINATION OF ICAM1, VCAM-1, E-SELECTIN, NOX2, NOX4, NOX5, IL-8, GM-CSF, MCP-1, PDE4 ISOFORMS, ERK1/2 AND P38 IN HUMAN PULMONARY ENDOTHELIAL CELLS AND EXPRESSION OF CD11B/CD18 AND ANION SUPEROXIDE IN NEUTROPHILS AND MONOCYTES FROM HEALTHY NON-SMOKERS, SMOKERS WITHOUT COPD, AND PATIENTS WITH MODERATE-SEVERE COPD. _x000D_ 2) HUMAN BRONchial EPITELIAL CELLS. ACTIVATION WITH LPS AND MEASUREMENT OF CYTOKINES/CHEMOKINES (IL-8, GM-CSF, IL-1, IFN, CCL5, CXCL10, CXCL11) AND STEROID-INDUCED ANTI-INFLAMMATORY GENES (GILZ, RGS2, MKP-1, CD200, CRISPLD2), PDE4 SUBTYPES (PDE4A TO D), PI3K, MUC5AC, DEUBIQUITINASA CYLD, AND P-P65 AND PKA-C1 EVOKED BY PDE4B OVERREGULATION. Measure OF THE RESPONSE OF GLUCORTICOIDE (GRE) AND EXPRESSION OF STEROICE RECEPTORS (GR and GR) in BEAS2B TNF-ACTIVATED CELULAS._x000D_ 3) EPITELY TRANSICATION to TGF- INDUCED Mesenchyma, ISTUDIATED AS REMODELING PATRON IN EPOC with EPITELIAL Markers Measurement (E-CADHERINA, ZO-1, CK18) And Mesenchymals (COLAGEN 1, -ACTINE, VIMENTINE), PDE4 ISOFORMAS, NOX1, NOX2, NOX4, NOX4 Y -CATENIN, GTP-RAC1, P-AKT, P-ERK1/2, and P-SMAD3. _x000D_ in ADDITIONAL EXPERIMENTS A LIVE EFFECT OF PDE4B INHIBITORS ON RATONS C57BL6J WT and KO for PDE4B and PDE4D will be studied. _x000D_ Etica: APPROVAL WILL BE OBTAINED FROM THE COMMITTEE ON INSTITUTIONAL ETHICS. THE NUMBER OF EXPERIMENTS WILL OPTIMISE THE USE OF HUMAN SAMPLES. _x000D_ innovation and knowledge transfer: OUR LABORATORY HAS CONTRIBUTED SIGNIFICANTLY TO THE PRECLINIC PROOF OF CONCEPT AND DOSSIER OF ROFLUMILAST, THE FIRST PDE4 INHIBITOR DRUG AUTHORISED FOR THE TREATMENT OF SEVERE COPD WITH FREQUENT EXACERBATIONS. (EMEA, 2010; FDA, 2011)._x000D_ CONCLUSIONS: THE RESULTS OF THIS PROJECT WILL CONTRIBUTE TO A BETTER UNDERSTANDING OF THE ANTI-INFLAMMATORY AND ANTI-REMODELING EFFECT OF SELECTIVE ISOFORM INHIBITORS PDE4 VS. ROFLUMILAST, AND THE BASIS OF THEIR COMBINATION WITH LABA AND INHALED STEROIDS IN THE PHARMACOLOGICAL TREATMENT OF COPD.

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