Scholarship 24/17783-2 - Neoplasias mamárias, Cardiotoxicidade - BV FAPESP
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MicroRNAs as therapeutics of cardiotoxicity in co-culture of embryonic stem cell-derived cardiomyocytes and human cardiac fibroblasts stimulated with doxorubicin.

Grant number: 24/17783-2
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Start date until: January 01, 2025
End date until: December 31, 2025
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Edilamar Menezes de Oliveira
Grantee:Alex Cleber Improta Caria
Supervisor: Diana Esperanca dos Santos Nascimento Andre
Host Institution: Escola de Educação Física e Esporte (EEFE). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Institution abroad: Universidade do Porto (UP), Portugal  
Associated to the scholarship:22/02339-4 - Physical training-regulated microRNAs as potential biomarkers and therapeutics of doxorubicin-induced cardiotoxicity in Breast Cancer: in vivo study, in vitro in iPS-derived cardiomyocytes and clinical with patient analysis, BP.PD

Abstract

Breast cancer is a type of cancer with high incidence and mortality among women. Several studies investigate strategies and tools to inhibit the development of the disease or, when already diagnosed, several therapies and treatments have been used. A well-established treatment in the clinic is through chemotherapy, with anthracyclines standing out. The anthracycline most used in breast cancer and in several other types of cancer is doxorubicin, however this drug induces multiple deleterious effects on the heart, generating cardiotoxicity. Cardiotoxicity promotes an increase in reactive oxygen species, inflammation, apoptosis, cardiac fibrosis, and these continue to be a main clinical limitation in the treatment of cancer patients who use doxorubicin. These associated processes induce diastolic and/or systolic dysfunction, reducing the left ventricular ejection fraction, generating heart failure in the long term. Some in vitro studies using doxorubicin in cardiomyocyte cultures have demonstrated effects very similar to those observed in humans, since this chemotherapy agent also induced an increase in reactive oxygen species, apoptosis and fibrosis in these cells. However, the effects of doxorubicin in a co-culture model containing cardiomyocytes derived from human embryonic stem cells together with human cardiac fibroblasts have not yet been observed in the literature. Also, little is known on the molecular regulation mediated by small non-coding RNAs, namely microRNAs, of the signaling pathways associated with the apoptotic process induced by this drug in this context. Herein, we propose to investigate the effects of doxorubicin on the modulation of microRNAs and regulation of apoptosis signaling pathways, to identify microRNAs differentially expressed and validate one or more signaling pathways associated with cardiotoxicity and apoptosis. Subsequently, a microRNA will be selected for in vitro validation through genetic modulation in this in vitro co-culture cardiac model towards the identification of a potential therapy to prevent and to treat cardiotoxicity in response to doxorubicin.Keywords: Breast cancer; doxorubicin; microRNAs; cardiotoxicity.

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