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Unveiling mechanisms of Marfan Syndrome-related cardiomyopathy

Grant number: 17/17186-0
Support Opportunities:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): January 10, 2018
Effective date (End): January 09, 2019
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Lygia da Veiga Pereira
Grantee:Juliana Borsoi Sant'Ana
Supervisor: Chris Denning
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: University of Nottingham, University Park, England  
Associated to the scholarship:16/16076-4 - Functional analysis of FBN1 mutations in human Pluripotent Stem-Cells (hPSCs), BP.DD


Caused by mutations in FBN1 (fibrillin-1), Marfan Syndrome (MFS) is an autosomal-dominant connective tissue disorder with prevalence between 1/3000 to 1/5000, in which the cardiovascular, skeletal, and ocular systems are mostly affected. Of these, cardiovascular manifestations, including dilation and dissection of the ascending aorta, calcification of mitral and aortic valves, thoracic aortic aneurism (TAA) and dilated cardiomyopathy (DCM), are responsible for morbidity and mortality in most cases. DCM is associated with moderate cardiac hypertrophy, ventricular dilation, systolic dysfunction, and progressive heart failure. While the prevailing view has always been that cardiac dysfunction in MFS results of aortic and/or valve disease, recent clinical and experimental data suggest it may be a primary consequence of fibrillin-1 mutations and one of the leading causes of mortality in patients. In vitro, we recently observed that MFS patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) display, upon endothelin-1 stimulation, a significantly higher expression of hypertrophic markers when compared to hiPSC-CMs from controls. These preliminary data suggest that MFS hiPSC-CMs are more susceptible to hypertrophic stress. Two molecular mechanisms are proposed to explain the occurrence of MFS: haploinsufficiency and dominant-negativity of fibrillin-1. Experimental and clinical data suggest that the type and severity of the phenotypic manifestations vary according to the mutation class. Using CRISPR/Cas9 gene editing system, we were able to generate distinct human pluripotent stem cell lineages harbouring haploinsufficiency or dominant-negative mutations in the FBN1 gene (hPSCsCRISPR). In this proposal, we aim to promote a detailed phenotypic characterisation of the hPSCCRISPR-CMs and to investigate the contribution of different molecular mechanisms in the pathophysiology of MFS-related cardiomyopathy. (AU)

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