Unveiling mechanisms of aberrant heart function in Marfan Syndrome (MFS)

• Grant number: 17/08014-1
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2018
• End date: October 31, 2019
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Agreement: University of Nottingham
• Principal Investigator: Lygia da Veiga Pereira
• Grantee: Lygia da Veiga Pereira
• Principal researcher abroad: Chris Denning
• Institution abroad: University of Nottingham, University Park, England
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Caused by mutations in FBN1 (fibrillin-1), Marfan Syndrome (MFS) is a clinically highly variable autosomal-dominant multi-system disorder. While dilated cardiomyopathy (DCM) was considered initially as only a secondary manifestation of the disease, recent clinical and experimental data suggest it may be a primary manifestation and one of thea leading causes of mortality in MFS patients. Data from mouse models also suggests that clinical heterogeneity may arise because of mutation type (haplo-insufficiency vs dominant-negative) and of mutations in modifier genes, such as the extracellular matrix regulator, HSPG2 (perlecan). In this 18 month proposal, we aim to produce human models of MFS by coupling human induced pluripotent stem cells (hiPSC), with Cas9/CRISPR gene editing, detailed cardiomyocyte phenotyping, glycobiology and mechanistic interrogation to provide greater understanding into the pathophysiology of the disease. The benefits will be to forge a new collaboration between investigators who work in complementary fields at the Universities of Sao Paulo and Nottingham, to promote researcher exchange and training, and to provide pilot data to submit a full application to the BBSRC-Brazil (FAPESP) joint funding of research during 2018, hence lead to a sustained effort in this area into the future. (AU)