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Role of sodium channel Nav1.7I228M variant in the physiopathology of chemotherapy-induced neuropathic pain

Grant number: 22/01459-6
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): October 03, 2022
Effective date (End): October 02, 2023
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal researcher:Thiago Mattar Cunha
Grantee:Francisco Isaac Fernandes Gomes
Supervisor abroad: Stephen Waxman
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: Yale University, United States  
Associated to the scholarship:19/14285-3 - Role of succinate/SUCNR1 signalling pathway in sensory neurons in neuropathic pain development, BP.DR

Abstract

Neuropathic pain is a disease of the somatosensory system that can result from different etiological factors such as mechanical, biological, metabolic, or chemical insults. Chemotherapeutic agents used to treat cancer can cause neuropathic pain (CINP) due to their neurotoxicity to primary sensory neurons, causing aberrant functioning of these cells and leading to long-lasting pain in cancer patients. This side-effect is among the leading causes of chemotherapy discontinuation, which is directly associated with cancer recurrence. Neuropathic pain develops in many but not all patients undergoing chemotherapy, which suggests a contribution by a genetic component that predisposes some individuals to CINP. A genetic component has also been found for other adult-onset painful disorders, including small fiber neuropathy, diabetes, and trigeminal neuralgia. Volage-gated sodium (Nav) channels have long been implicated in nociceptive input transduction and transmission/propagation. Several gain-of-function (GOF) mutations in voltage-gated sodium channels have been linked to human pain syndromes, including adult-onset diseases. Animal models in which transgenic mice carry a GOF mutation in a Nav channel and those that carry knockout alleles of the specific channel are invaluable in delineating the contribution of this genetic component in these pain disorders. Although the Nav1.7I228M knock-in mouse line, which carries a GOF mutation initially identified in patients with small fiber neuropathy, did not manifest increased pain in response to acute pain, compared to WT mice, it is not known whether this variant predisposes this mouse to increased pain in a more chronic disease model. As such, this project aims to study the effects of the sodium channel variant Nav1.7I228M in the pathophysiology of chemotherapy-induced neuropathic pain. To achieve this, behavioral, structural, and electrophysiological approaches will be employed to examine whether this variant in Nav1.7 acts as a risk factor for paclitaxel-induced CINP. Underpinning genetic variations that lead to pain resistance during chemotherapy would allow novel therapeutic approaches to treat neuropathic pain. (AU)

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