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Crosstalk among signaling pathways of the TNF-alpha receptor, cannabinoid receptor subtype 1 (CB1) and transient receptor potential vaniloid 1 (TRPV1) to modulate inflammation and proliferative response in cultured corneal epithelial cells

Grant number: 12/06045-3
Support type:Regular Research Grants
Duration: August 01, 2012 - July 31, 2014
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal researcher:Eduardo Melani Rocha
Grantee:Eduardo Melani Rocha
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers:Flavia Leao Barbosa ; Peter Sol Reinach


In the corneal epithelium, the outcomes of injury-induced wound healing are affected by the responses induced by transient receptor potential vaniloid 1 (TRPV1) activation. This is evident from a comparison of the wound healing response to an alkali burn in wild type (TRPV1+/+) (WT) with that in TRPV1 knockout (TRPV1-/-) (KO) mice. Occasionally, the globes of WT were even perforated. However, in the TRPV1 KO mice the wound healing outcome is much improved. These results indicate that severe injury increases the formation of endogenous metabolites, which persistently activate TRPV1 channels. Their activation contributes to dysregulated inflammation that delays or prevents wound closure and restoration of corneal transparency. Accordingly, severe injury releases endogenous endocannabinoid and endovaniloid metabolites leading to persistent TRPV1 activation and dysregulated inflammation. Our overall testable hypothesis is: TRPV1-induced increases in inflammatory mediator release are modulated by CB1 control of TRPV1 activation and TNF±R-induced modification of TRPV1-linked (transforming growth factor activated kinase 1) TAK1 activation. Our project using HCEC has two aims: 1) Given that CB1 interacts with TRPV1, we will determine if this occurs through TRPV1 inhibition and/or downstream modulation of TRPV1 linked signaling pathway activation. 2) Given that both TNF± and TRPV1 mediate responses through transient TAK1 activation, we will determine the mechanisms regulating TAK1 phosphorylation (i.e. activation) status. In order to elucidate the cell signaling pathways mediating control by TRPV1 of inflammation, we use for this purpose cultured human corneal epithelial cells (HCEC), western blotting and ELISA assays. (AU)

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