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Endothelial phenotype as determinant of genotype/phenotype relationship in Marfan Syndrome

Grant number: 19/26007-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2021
Effective date (End): July 31, 2023
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Lygia da Veiga Pereira
Grantee:Patricia Nolasco Santos
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID

Abstract

Marfan Syndrome (MFS) is an autosomal dominant connective tissue disease that primarily affects skeletal, ocular and cardiovascular systems, been Aortic Aneurysm responsible for most morbidity and mortality. MFS is caused by mutations in the fibrillin-1 gene (FBN1), one of the main structural components of the extracellular matrix and responsible for regulating TGF-² activity. MFS has important clinical variability and still unclear the association between genotype and phenotype. One factor potentially associated with this variability is mutation class, Haploinsufficient (HI) or Negative Dominant (DM), which is known to correlate with MFS severity. However, there is no understanding of integrative mechanisms common to different aspects of disease. Endothelial dysfunction is an emerging mechanism and may be associated with aneurysms development in MFS, although it is not clear whether increased NO is a cause or consequence of dilation. Our hypothesis is that the endothelial phenotype is important to understanding the relationship between distinct genotypes and cardiovascular phenotypes, both by markers of endothelial dysfunction and by altered communication between endothelial cells and smooth muscle cells. The main aim of this project is to validate signaling pathways and paracrine function of endothelial cells in a model of human induced Pluripotent Stem Cells (hiPSCs) carrying mutations classified as HI and DN that cause MFS. Specific aims are: 1) to validate the model of hiPSCs-derived Endothelial Cells (EC) and Smooth Muscle Cells (SMC) carrying mutations classified as HI and DN; 2) to investigate, in hiPSCs-derived EC (obtained in objective 1) subjected to shear stress, the influence of distinct MFS-causing mutations on biochemical, molecular and functional EC markers; 3) establish a co-culture model between EC-hiPSC and SMC-hiPSC and evaluate the influence of HI and DN mutations on signaling dynamics between the two cell types. These studies may contribute to elucidate a new disease mechanism, endothelial dysfunction, as a determinant of phenotypicaspects of MFS. (AU)

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