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Characterization and development of new TrkA and PKMzeta pathway modulators in inflammatory and chronic pain.

Grant number: 23/12738-6
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): January 01, 2024
Effective date (End): January 31, 2025
Field of knowledge:Interdisciplinary Subjects
Principal Investigator:Camila Squarzoni Dale
Grantee:Bianca Neofiti Papi
Host Institution: Instituto de Ciências Biomédicas (ICB). 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

Opioides have an addictive effect generate tolerance upon prolonged use causing unwantedside effects. Thus, there is a great need to search for new analgesic substitutes. To this end,understanding the signaling pathways that lead to pain can help develop new non-opioidanalgesics. Inflammatory pain begins with the secretion of nerve growth factor (NGF) andactivation of its high affinity receptor, Tropomyosine kinase A (TrkA) in sensory peripheralneurons. Through neuronal depolarization this signal is transmitted to the central nervous system(CNS). Due to the fact that TrkA is also a key kinase involved in the development of the sensorynervous system several mutations lead to Congenital Insensitivity to Pain with Anhidrosis (CIPA),which is the lack of nociceptive painChronic pain involves Long-term potentiation (LTP), that is the strengthening and formation ofmore durable synapses, a process also important for memory and learning. This process leads toremodeling of the brain mainly of the anterior cingulate cortex (ACC) in the case of chronic pain.One of the key kinases involved in the establishment of LTP is Protein kinase C M] (PKM].However, the specific role of this kinase in LTP has still not been elucidated.New strategies for the development of new analgesics have TrkA as a target of the peripheralnervous system and at the central level inhibition of remodeling is desirable. Thus, in the presentproject we aim at studying signaling pathways involved in the transmission of signals ofinflammatory nociceptive pain by NGF and TrkA and at the central level pathways that leadto the establishment of LTP, and chronic pain mediated by PKM] To this end, we will studyTrkA, mutations found in patients with CIPA, mapping molecular changes caused by themutations in pain signal transduction pathways, and in the development of the sensorynervous system (using chicken embryos). We will identify and characterize newpharmacological modulators of the activity of TrkA that have an effect on inflammatorypain. We will determine the epigenetic factors and signaling pathways that modulate theexpression of PKM]and how these factors influence the expression of the kinase inchronic pain. We will identify PKM]substrates and binding proteins validating their role in brainremodeling and chronic pain.

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