Cell signaling pathways mediated by PARs and Kallikreins in MDPC-23 Odontoblastic cell line

• Grant number: 24/05260-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2024
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Enzymology
• Principal Investigator: Fábio Dupart Nascimento
• Grantee: Thereza Camila Kleinpaul Ferreira
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The PAR family of receptors plays a vital role in many processes like hemostasis, inflammation, embryonic development, and the pathogenesis of some types of cancer. Different genes code all four members of this receptor family, and their expressions vary based on the species and cell type being studied. The activation of PARs occurs due to the proteolytic cleavage of a specific peptide sequence in the extracellular portion of the receptor's N-terminal region, which is irreversible. The PAR receptors family is responsible for mediating important responses in the processes of hemostasis, inflammation, embryonic development, and the pathogenesis of some types of cancer. All four members of the PAR family are encoded by distinct genes, which present expression profiles that vary with the species and cell type analyzed. The activation of PARs begins with the irreversible proteolytic cleavage of a specific peptide sequence in the N-terminal region of the extracellular portion of the receptor. The peptide released by this hydrolysis reaction starts to have the function of an antagonist, and when it binds to a specific region located on the surface of the second extracellular loop, of the same or another receptor, it promotes conformational changes in the molecule structure, which ends up triggering broad and diverse intracellular signaling cascades. More, there is a highly specific group of serine proteases that can activate PARs, among them are thrombin, plasmin, tissue kallikreins, factor Xa, and activated protein C (PCA), as well as matrix metalloproteinases-1 (MMP1), which can cause distinct physiological effects, such as inflammatory and anti-inflammatory responses. Given this wide range of activating proteases, PARs are responsible for mediating cell signaling in different pathophysiological processes, which include platelet activation, positive regulation of the activity of numerous endothelial and smooth muscle cells, regulation of neuronal functions, and fine-tuning of responses. inflammatory. Despite numerous studies highlighting the importance of a better understanding of the pathophysiological processes that involve the progression of caries disease, only in 2017 did our group publish the first article in the literature showing that PAR1 and PAR2 are modulated in odontoblasts during the inflammatory process triggered by caries. This work showed that thrombin, a natural activator of PAR1, induces the phosphorylation of ERK ½ in a time-dependent manner. Furthermore, we showed that one of the possible roles of PARs 1 and 2 is related to the production of secondary dentin and the control of remineralization of the dental element in the presence or absence of harmful stimuli. This proposal aims to continue this promising line of research already underway in our group.