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Kinin B1 receptor Activity Modulation and IL-6 Trans-Signaling in the Immunometabolism Via Protease Activator Receptor-1

Grant number: 18/11514-9
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): September 01, 2018
Effective date (End): August 31, 2019
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Ronaldo de Carvalho Araújo
Grantee:Leandro Ceotto Freitas Lima
Supervisor: Michael Bader
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Research place: Max Planck Society, Berlin, Germany  


The glucose metabolism is closely related to an impairment of several chronic diseases, as obesity, diabetes and the metabolic syndrome. Kallikrein-kinin system (KKS) has been involved in different metabolic processes, demonstrated by knockout mice that are resistant to obesity. The kinin receptors, B1 (B1R) and B2 (B2R) are responsible for mediating the biological responses from the precursor kininogens peptides. Bradykinin or kallidin are agonists for B2Rs whereas their carboxypeptidase-generated metabolites, des-Arg9-bradykinin or des-Arg10-kallidin are specific agonists for B1Rs. Moreover, the KKS is activated by another proinflammatory stimulus: physical exercise, and interleukin 6 (IL-6) is the major cytokine released during this event. IL-6 is a pleiotropic cytokine, constantly related to a stressor event. It participates in the inflammatory processes and modulates insulin sensitivity, affecting the energetic metabolism. Also, under inflammatory conditions and/or in hyperglycemic stress, the protease activated receptors (PARs) signaling contributes to healing responses after injury, by promoting cytokine activity, as IL-6 production and release. PARs are activated by mechanism that involves recognition of the receptor by a protease, acting as a "tethered ligand". Based on the primary aminoacid sequence of B1R, which displays a region similar to the PAR1 agonist (aminoacid sequence TFLLRS), we hypothesize that the catalytic PAR1 domain could interact with B1R, leading to a modulation of B1R activity. Indeed, we hypothesized the catalytic PAR1 domain could interact with B1R inhibiting its activity. If this hypothesis is confirmed, both PAR1 and B1R could be a potential target to future pharmacological therapies.

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