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The effects of FAK inhibition on the ATM/Chk2/p53/p21 signaling pathway during the DNA damage response of cardiomyocytes treated with doxorubicin

Grant number: 23/16443-0
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2024
Effective date (End): February 28, 2025
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Aline Mara dos Santos
Grantee:Lara Basseres Novais
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Doxorubicin (dox) induced cardiotoxicity is one of the most important side effects of this chemotherapeutic drug, seeing as it can lead to oncological patients developing cardiomyopathies. Dox produces free radicals and inhibits topoisomerase II, which results in several DNA breaks followed by genotoxic stress culminating in cardiomyocyte death. Multiple studies show that Focal Adhesion Kinase (FAK) has an overall pro-survival effect on cardiomyocytes during dox treatment, and is translocated to the nucleus during genotoxic stress, having a role promoting p53 degradation. These findings indicate that FAK may have a relevant function in DNA damage response (DDR) signaling in cardiomyocytes, however, the specific mechanisms through which FAK operates in this pathway is still unknown. In this project we propose to study the relation between FAK and the proteins involved in the ATM/Chk2/p53/p21 DDR signaling pathway. By inhibiting FAK in parallel with dox treatment we will investigate: (i) the modulation of the number of c-H2AX sites and alterations of the subcellular locations of ATM, Chk2 and p53, as well as their co-localization with FAK, using superresolution structured illumination microscopy (SR-SIM); (ii) alteration in ATM, Chk2, p53 and p21 expression and activation through western blotting and qPCR; and (iii) the modulation of cell viability using an MTT assay. By conducting these experiments we expect to increase our understanding of how FAK affects the DDR response in cardiomyocytes.

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