Effects of CIPA-associated mutations in TrkA on the pain signaling pathways and development of nociceptive neurons

• Grant number: 20/13929-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2020
• End date: November 30, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Deborah Schechtman
• Grantee: Felipe Monteleone Vieceli
• 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
• Associated scholarship(s): 23/04849-2 - In vivo analysis of TrkA function in chicken embryos, BE.EP.PD

Abstract

The activation of the receptor Tropomyosin-Related Kinase A (TrkA/NTRK1) by nerve growth factor (NGF) initiates pain signaling and is a relevant target of alternative therapies to using opioids, which can lead to addiction. Further, the activation of the TrkA/NGF axis is required for the embryonic development of Dorsal Root Ganglia (DRGs), which contain cell bodies of nociceptive neurons responsible for pain sensation. Patients with Congenital Insensitivity to Pain with Anhydrosis (CIPA) have mutations in the NTRK1 gene and, in some cases, developmental defects in nociceptive and autonomic nerves. In this project, we aim to evaluate the importance of mutations found in CIPA for TrkA role in the function and development of nociceptive neurons. To achieve this, we will use cell lines expressing wild-type or mutated TrkA to quantify and compare its phosphorylation kinetics, activation of its partner PCL-gamma, and intracellular calcium release. In embryonic development, we will study the formation of DRGs in chicken embryos overexpressing wild-type or mutated TrkA. These results will be used to design synthetic peptides that block the interaction of TrkA with PLC-gamma, and we will validate their activity in vitro and in vivo. Our results will support conclusions on the importance of specific TrkA sites for pain signaling and GRD development and may inform the development of novel pain therapies based on blocking particular interactions. (AU)

Scientific publications

(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)

PRAMIO, DIMITRIUS TANSINI; VIECELI, FELIPE MONTELEONE; VARELLA-BRANCO, ELISA; GOES, CAROLINA PURCELL; KOBAYASHI, GERSON SHIGERU; PELEGRINA, DIOGO VIEIRA DA SILVA; MORAES, BEATRIZ CAROLINE DE; EL ALLAM, AICHA; DE KUMAR, BONY; JARA, GABRIEL; et al. DNA methylation of the promoter region at the CREB1 binding site is a mechanism for the epigenetic regulation of brain-specific PKM zeta. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS, v. 1866, n. 1, p. 13-pg., 2023-01-25. (19/06982-6, 15/24046-5, 20/13929-1, 20/16204-8, 15/17812-3)