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

Grant number: 20/13929-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): December 01, 2020
Effective date (End): November 30, 2022
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal researcher:Deborah Schechtman
Grantee:Felipe Monteleone Vieceli
Home 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 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)

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