Effect of constitutive inhibition of QEP peptide interaction partners on hypersensitivity signaling in peripheral somatosensory neurons

• Grant number: 24/18174-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2025
• End date: August 31, 2028
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Deborah Schechtman
• Grantee: Alexandre Martins do Nascimento
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/06982-6 - Characterization and development of new modulators of the TrkA and PKMzeta pathways in inflammatory and chronic pain, AP.TEM

Abstract

The permeable phosphopeptide TAT-pQYP has been shown to reverse acute nociception in inflammatory models by inhibiting the anchoring of Phospholipase-Cg (PLCg) to the phosphorylated Y785 of Tropomyosin kinase A (TrkA), thereby inhibiting the phosphorylation and activation of the lipase by TrkA and peptide signaling in the nociceptors of the dorsal root ganglion (DRG). The hypothesis of this project is that PLCg and other interaction partners of the peptide are essential for the sensitization of peripheral nociceptors. Thus, we aim to unravel the different signaling pathways modulated by the peptide in different hypersensitivity models, elucidating peripheral mechanisms that lead to these phenotypes. Mice will be inoculated with a retrograde selective adenovirus for neural projections, which will promote constitutive expression of the QEP peptide (analogous to pQYP), and later used to assess the impact of constitutive inhibition of its interaction partners on the following hypersensitivity phenotypes: inflammatory nociception by carrageenan, neurogenic stimulation of transient potential channels (TRP), and chronic osteoarthritis-induced nociception. The DRG of the animals will be evaluated for the expression of inflammatory markers and the impact on the activation of various kinases. We will also perform a proteomic analysis of QYP/QEP interaction partners in a mouse cell line. The list of interaction partners will be explored using bioinformatic tools aimed at validating pro-nociceptive signaling pathways in primary DRG cultures from neonates, and the targets/interactions can be evaluated in the established in vivo models and in collected tissues. Overall, it is expected to characterize how hypersensitivity phenotypes are impacted by the constitutive expression of the QEP peptide, as well as broadly understand the relationship of the signaling pathways impacted by the peptide in the observed phenotypes. (AU)