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Involvement of the kallikrein-kinin system in the pathophysiology of Fabry Disease from patient iPSC-derived cardiomyocytes

Grant number: 23/18058-7
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): February 01, 2024
Effective date (End): January 31, 2025
Field of knowledge:Biological Sciences - Biology
Principal Investigator:João Bosco Pesquero
Grantee:Jéssica Laís de Oliveira Branquinho Pennacino
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:20/14635-1 - Modeling of monogenic diseases for physiopathological studies and pharmacological tests using specialized cells derived from iPSCs, AP.TEM


Fabry disease (FD) is an inborn error of metabolism caused by mutations in the gene for the enzyme ±-galactosidase A (GLA) located on the X chromosome. These mutations result in deficiency of the enzyme ±-galactosidase A (±-Gal A), causing the accumulation of globotriaosylceramide (Gb3). ±-Gal A deficiency results in pathogenic changes in several organs, including Fabry cardiomyopathy, with a mechanism not yet established and being the most frequent cause of death in patients with this disease. Currently, the treatment of FD is restricted to a few drugs, which are extremely expensive and have limited effectiveness. This scenario opens space for research into new therapeutic approaches for a better prognosis of FD, such as the activation of the kallikrein-kinin system (KKS). The presence of this system in different tissues of the cardiovascular system led us to speculate that the activation of kinins and their receptors could be an important factor in the pathophysiology of FD. Therefore, we propose to develop an in vitro model to study the pathophysiology of FD in immortalized cardiomyocyte, derived from iPSCs and organoids. The iPSCs will originate from blood cells from patients with the disease or from mutations in the GLA gene induced by the CRISPR-Cas9 system. The differentiated cells will be subjected to KKS activation protocols, evaluated by Ca2+ mobilization. Cardiomyocytes will be characterized through analyzes of cell viability and permeability, enzymatic activity, Gb3 accumulation and electrophysiology. The molecular effects will be evaluated by pharmacological analyzes, gene expression (transcriptome and Real-Time), enzymatic activity (ACE and ACE2), immunofluorescence and protein expression. The implementation of an in vitro model of cardiomyocytes carrying mutations in GLA and the study of their possible impact on the kallikrein-kinin system could then open perspectives for testing new drugs and provide important pharmacogenomic information.

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