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Analysis of angiotensin I converting enzyme activity in an animal model with altered neuronal positioning

Grant number: 23/14528-9
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): December 01, 2023
Effective date (End): May 31, 2024
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Mirian Akemi Furuie Hayashi
Grantee:Ananda Luiza Andrade Silva
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:19/13112-8 - Study of molecular and cellular mechanisms involved in mental disorders: clinical and animal models analysis, AP.TEM

Abstract

Angiotensin I converting enzyme (ACE) is a dipeptidyl carboxypeptidase with a key function in the renin angiotensin system (RAS), whose function in the central nervous system (CNS) has only recently attracted the attention of researchers. Interestingly, in addition to being primarily responsible for the conversion of angiotensin I into the hypertensive and pro-inflammatory agent angiotensin II, ACE also cleaves neuropeptides such as neurotensin (NT), which is essential for the response to antipsychotics used to treat patients with schizophrenia (SCZ), and has been described as a potential endogenous antipsychotic. SCZ is a highly prevalent psychiatric disorder with highly debilitating clinical characteristics. Although studies with animal models and clinical studies in patients with SCZ have contributed to confirming that there are significant changes in the activity of oligopeptidases at the beginning and throughout these mental disorders, it has not yet been possible, to date, to the identification and characterization of molecular and/or cellular pathways that may be involved in the etiology and pathophysiology of this psychiatric disorder. The use of a good animal model is undoubtedly of fundamental importance for this purpose. Therefore, an animal model that overexpresses the DISC1 (Disrupted-In-Schizophrenia 1) gene and that presents changes in the positioning of the neuronal body will be used to validate the biochemical changes already described in another animal model for SCZ and also in clinical studies with patients, aiming to correlate these new data with the findings already obtained in studies conducted so far by the group, and which have allowed for now to demonstrate changes in ACE activity, both in patients with chronic SCZ, undergoing treatment with antipsychotics, and in individuals undergoing first psychotic episode even before treatment, compared to healthy controls, paired for sex and age. In these studies, it was possible to verify that the genetic differences between the animal models previously used or between individuals with SCZ and their respective controls constitute important limitations for studies at the molecular and/or cellular level. Therefore, using transgenic animal models, we hope that it will be possible to contribute more effectively by generating new information that allows the understanding of the molecular mechanisms involved in the etiopathology of severe mental disorders, such as SCZ.

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