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In vitro models to study the neuropathophysiology of Fabry disease

Grant number: 23/00063-4
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): February 01, 2023
Effective date (End): January 31, 2024
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:João Bosco Pesquero
Grantee:Priscila Nicolicht de Amorim
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 GLA gene located on the X chromosome. Defects in this gene lead to ±-galactosidase A (±-Gal A) deficiency, an enzyme responsible for degrading glycosphingolipids, mainly globotriaosylceramide (Gb3). ±-Gal A is present in all tissues, and its deficiency results in progressive multisystem disease. SCD covers a wide clinical phenotypic spectrum, mainly affecting cardiac, renal, gastrointestinal and cerebrovasculares systems. Cerebrovascular and neuropsychiatric symptoms are described in patients with SCD, however, the pathophysiological bases of SCD in the central nervous system are poorly understood. We propose to develop an in vitro model to study the neuropathophysiology of SCD through the use of induced pluripotent stem cells (iPSCs). First, we will use the CRISPR/Cas9 technique to edit the GLA gene of the iPSCs, these cells will be characterized for the efficiency of inducing mutations, absence of off-targets and pluripotency potential, as well as for the deficiency of enzymatic activity of ±- Gal A. Then the cells will be differentiated into astrocytes and brain endothelial cells, and the accumulation of Gb3, as well as cell survival will be evaluated. Finally, transcriptomics and proteomics of both edited cells and wild-type cells will be performed in order to analyze the possible impact of ±-Gal A deficiency on the expression of mRNAs and proteins that may be related to cerebrovascular and neuropsychiatric changes found in patients with DF. With this project, we will take an important step in the study of the neuropathophysiology of SCD, a topic that has been little explored, but of vital importance for the treatment of patients.

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