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A função do receptor de estrógeno acoplado à proteína G (GPER) astrocitário na angiogênese e neuroproteção após modelo de Isquemia Cerebral Transitória em camundongos

Grant number: 22/08767-8
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): December 01, 2022
Effective date (End): July 31, 2027
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Carolina Demarchi Munhoz
Grantee:Paloma Marinho Jucá
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cardiovascular diseases are the leading cause of death in the world and include cerebrovascular diseases such as cerebrovascular accident (CVA). Most of the risk factors for stroke are modifiable, but non-modifiable factors, such as the individual's sex and age, interfere with their predisposition to suffer the accident. Epidemiological studies suggest that estrogen (mainly 17²-estradiol), a female sex hormone, has neuroprotective activity, but its late and feminizing effects limit therapeutic activity, especially in males. The G protein-coupled estrogen receptor (GPER) and its selective agonist, G1, make the estrogen response a more universal pharmacological alternative, as rapid and non-feminizing responses are promoted. Previous studies by our group, in an in vitro model, demonstrate that the absence of signaling via GPER makes cells more susceptible to the deleterious effects of ischemia, an effect that seems to be astrocyte-dependent. Thus, this study seeks to elucidate how the modulation of astrocytic GPER affects the in vivo prognosis of the brain after ischemia and has the potential to introduce G1 as a pharmacological alternative to reduce post-stroke sequelae. For this, we will use animals submitted to the model of ischemia by transient occlusion of the middle cerebral artery (MCAO) and we will evaluate the neuroprotective effect of the GPER agonist on motor, cognitive and molecular alterations after ischemia. Furthermore, GPER expression will be specifically silenced in astrocytes, in order to test our central hypothesis that G1 has a neuroprotective effect in vivo and that this effect is astrocyte-dependent. (AU)

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