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Analysis of the effect of heterologous expression of hSPAG11B alternative splice variants in the development of inflammatory arthritis in the knee joint of wild-type and F2rl1 (PAR2) knockout mice

Grant number: 12/07784-4
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Start date: August 01, 2012
End date: July 31, 2013
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Maria Christina Werneck de Avellar
Grantee:Alexandre Denadai Souza
Supervisor: Nathalie Vergnolle
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Institution abroad: Université Paul Sabatier - Toulouse III, France  
Associated to the scholarship:09/12375-3 - Role of the protein SPAG11 in the modulation of experimental arthritis, BP.PD

Abstract

The gene of human sperm-associated antigen 11 (hSPAG11) is localized within a ²-defensin cluster in the chromosome 8p23. Alternative splicing mechanism involving the differential recruitment of 2 promoters and multiple exons results in 7 distinct transcripts in humans (hSPAG11A, B, C, D, E, G and H). While a role for SPAG11 in innate host defence and reproduction has emerged, the mechanism of action is unknown. Otherwise, a recent in vitro study characterized hSPAG11D and its N-terminal domain (shared with the isoform hSPAG11C), as potent inhibitors of the serino-proteinase tryptase, an important mediator of inflammation that activates Proteinase-Activated Receptor 2 (PAR2). The aim of the present study is to investigate whether the heterologous expression of hSPAG11C and D modulates the development of experimental arthritis by inhibiting the pro-inflammatory pathway tryptase/PAR2. Over-expression of recombinant hSPAG11 isoforms in the mouse knee joint will be achieved by an intra-articular transduction of lentiviral particles in association with Vpx-VLPs, where the genes encoding to hSPAG11 isoforms were inserted by directional cloning. Male wild-type or F2rl1 (PAR2) knockout C57BL/6 mice over-expressing recombinant hSPAG11C, D or E (the former as control) will be submitted to mBSA/IL-1²-induced arthritis. After all, several inflammatory parameters will be analysed, such as oedema formation, histopathology, myeloperoxidase and serino-protease activities and the pattern of cytokines Th1/2 and 17. (AU)

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Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BAUTZOVA, TEREZA; HOCKLEY, JAMES R. F.; PEREZ-BEREZO, TERESA; PUJO, JULIEN; TRANTER, MICHAEL M.; DESORMEAUX, CLEO; BARBARO, MARIA RAFFAELLA; BASSO, LILIAN; LE FAOUDER, PAULINE; ROLLAND, CORINNE; et al. 5-oxoETE triggers nociception in constipation-predominant irritable bowel syndrome through MAS-related G protein-coupled receptor D. SCIENCE SIGNALING, v. 11, n. 561, p. 13-pg., . (12/07784-4)
YSHII, LIDIA M.; MANFIOLLI, ADRIANA O.; DENADAI-SOUZA, ALEXANDRE; KINOSHITA, PAULA F.; GOMES, MARCELO D.; SCAVONE, CRISTOFORO. Tumor necrosis factor receptor-associated factor 6 interaction with alpha-synuclein enhances cell death through the Nuclear Factor-kB pathway. IBRO REPORTS, v. 9, p. 218-223, . (12/07784-4, 11/10303-5, 14/24951-7, 09/12375-3, 18/01308-2, 16/07427-8, 19/10044-1, 18/14289-6, 13/22196-4)
BAUTZOVA, TEREZA; HOCKLEY, JAMES R. F.; PEREZ-BEREZO, TERESA; PUJO, JULIEN; TRANTER, MICHAEL M.; DESORMEAUX, CLEO; BARBARO, MARIA RAFFAELLA; BASSO, LILIAN; LE FAOUDER, PAULINE; ROLLAND, CORINNE; et al. 5-oxoETE triggers nociception in constipation-predominant irritable bowel syndrome through MAS-related G protein-coupled receptor D. Science Signaling, v. 11, n. 561, . (12/07784-4)
DENADAI-SOUZA, ALEXANDRE; RIBEIRO, CAMILLA MOREIRA; ROLLAND, CORINNE; THOUARD, ANNE; DERAISON, CELINE; SCAVONE, CRISTOFORO; GONZALEZ-DUNIA, DANIEL; VERGNOLLE, NATHALIE; WERNECK AVELLAR, MARIA CHRISTINA. Effect of tryptase inhibition on joint inflammation: a pharmacological and lentivirus-mediated gene transfer study. ARTHRITIS RESEARCH & THERAPY, v. 19, . (12/07784-4, 09/12375-3)