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Identification of epigenetic mechanisms induced by stress which modulate endocannabinoid signaling and neuroimmunological mechanisms as new therapeutic targets to treat the posttraumatic stress disorder (PTSD)

Grant number: 17/19731-6
Support type:Research Grants - Young Investigators Grants
Duration: February 01, 2019 - January 31, 2023
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal researcher:Sabrina Francesca de Souza Lisboa
Grantee:Sabrina Francesca de Souza Lisboa
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers:Francisco Silveira Guimaraes ; John F Sheridan ; Jonathan Godbout ; Leonardo Resstel Barbosa Moraes ; Sâmia Regiane Lourenço Joca
Associated scholarship(s):21/01656-3 - Evaluation of the involvement of histone acetylation in behavioral changes and in the endocannabinoid system after exposure to trauma in mice, BP.MS
21/02139-2 - Evaluation of the possible facilitation of the response to the extinguishment of conditioned fear after trauma by drugs that alter epigenetic mechanisms., BP.IC
21/00335-9 - Training in techniques for care, maintenance and reproduction of transgenic lines of Cre-LoxP mice, BP.TT
+ associated scholarships 20/15951-4 - Training in cell culture techniques, BP.TT
19/19226-5 - Evaluation of the involvement of endovanilloid and endocannabinoid systems in behavioral and plastic consequences after trauma exposure in mice, BP.MS
19/12830-4 - Evaluation of the possible facilitation of the conditioned fear extinction response after trauma by drugs that modulate the endocannabinoid signaling, BP.IC
19/05013-0 - Identification of epigenetic mechanisms induced by stress which modulate endocannabinoid signaling and neuroimmunological mechanisms as new therapeutic targets to treat posttraumatic stress disorder (PTSD)., BP.JP - associated scholarships


The posttraumatic stress disorder (PTSD) can be developed after exposure to severe trauma, resulting in debilitating symptoms, such as impaired ability to extinguish aversive memories. Notwithstanding the PTSD severity, the pharmacotherapy is limited and inefficacious in several patients, evidencing the need for identification of trauma-altered mechanisms which could act as biomarkers, in order to provide potential novel therapeutic targets. The neuroimmune and endocannabinoid (ECB) systems are altered in response to trauma exposure in humans and animal models. Evidence suggests interaction between those systems in the modulation of the stress response, such as modulation of microglial activation and synaptic plasticity, which could result in dysfunctional synapses. One of the alterations in the microglia which may contribute to these effects is the activation of the NLRP3 inflammasome. Epigenetic mechanisms can modulate the expression of mediators from neuroimmune and ECB systems, contributing to the development of behavioral consequences of trauma exposure. The aim of this project is to investigate if trauma-induced high levels of ECBs and microglial NLRP3 inflammasome activation modulate the ECB system and alter the synaptic plasticity and activity, resulting in behavioral deficits. Moreover, the participation of epigenetic mechanisms in such effects will also be investigated. We will use in vitro e in vivo approaches to study molecular mechanisms, as well as behavioral and neuroplastic changes in naïve and stressed mice. To do that, we intend to perform pharmacological modulation of ECB signaling and epigenetic mechanisms, genetically modified mice, and cutting edge technologies on molecular biology. The results from this study may contribute to a better comprehension of PTSD neurobiology and, potentially, provide biomarkers after trauma exposure. Moreover, results could point out therapeutic alternatives for PTSD treatment in those patients that are resistant to conventional treatment. (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)
HARTMANN, ALICE; LISBOA, SABRINA FRANCESCA; SONEGO, ANDREZA BUZOLIN; COUTINHO, DEBORA; GOMES, FELIPE VILLELA; GUIMARAES, FRANCISCO SILVEIRA. Cannabidiol attenuates aggressive behavior induced by social isolation in mice: Involvement of 5-HT1A and CB1 receptors. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 94, AUG 30 2019. Web of Science Citations: 0.
HARTMANN, ALICE; FASSINI, ALINE; SCOPINHO, AMERICA; CORREA, FERNANDO M. A.; GUIMARAES, FRANCISCO S.; LISBOA, SABRINA F.; RESSTEL, LEONARDO B. M. Role of the endocannabinoid system in the dorsal hippocampus in the cardiovascular changes and delayed anxiety-like effect induced by acute restraint stress in rats. JOURNAL OF PSYCHOPHARMACOLOGY, v. 33, n. 5, p. 606-614, MAY 2019. Web of Science Citations: 0.

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