Role of cytoplasmic DNA sensor, STING, in cisplatin-induced peripheral neuropathic pain development

• Grant number: 21/09854-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2022
• End date: July 31, 2023
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Thiago Mattar Cunha
• Grantee: Fabio Bonifacio de Andrade
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Pain perception is necessary for the survival and self-preservation of an organism. However, situations that affect the somatosensory system leads to pathologic chronic pain development. Cisplatin, a chemotherapeutic agent widely used for Cancer treatment, has as its major side effect the neurotoxicity, that results in peripheral neuropathy. This debilitating condition affects more than 90% of patients and can persist even though the treatment is over. Cisplatin-Induced Peripheral Neuropathy (CIPN) pathophysiology is characterized, in addition to direct cytotoxic activity, by a range of other alterations that can contribute to nociceptors injury. Emerging evidence demonstrates that cisplatin treatment provokes neuropathic pain in mice through mitochondrial damage in sensorial neurons. Moreover, mitochondrial damage can induce cytoplasmic escape of mitochondrial DNA (mtDNA), leading to activation of the DNA sensor STING. We therefore hypothesize that cisplatin-induced mitochondrial damage in neurons could stimulate the cytoplasmic escape of mtDNA resulting in STING activation and, hence, the production of inflammatory cytokines that are relevant for neuropathic pain development. Previous behavioral data from our lab demonstrate that STING contributes to Neuropathic Pain Induced by Cisplatin (NPIC) development. Thus, we aimed to investigate the role of STING in NPIC once studies evaluating this association are inexistent. To address this aim, we are going to use in vivo approaches in which STING will be down-regulated by genetic techniques, and also in vitro approaches. The understanding of the mechanisms and molecules involved in CIPN development can reveal new targets for pharmacological interventions. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

ANDRADE, Fabio Bonifacio de. Role of cytoplasmic DNA sensor, STING, on development and maintenance of neuropathic pain induced by cisplatin. 2023. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.