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Mechanisms and implications of the mTORC1 signaling pathway in the cardiovascular phenotype of Marfan Syndrome

Grant number: 14/24511-7
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2015
Effective date (End): May 31, 2019
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Francisco Rafael Martins Laurindo
Grantee:Patricia Nolasco Santos
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

The Marfan syndrome (SMF), caused by mutations in the fibrillin-1 gene elastic matrix, whose main phenotype aortic aneurysms, valvular heart disease and cardiomyopathy. Several mechanisms are linked to the pathophysiology of SMF, especially signaling via angiotensin AT1 receptor, TGF-² and its non-canonical pathway involving the kinase ERK. Studies from our group indicate that redox pathways may have a protective role paradoxically, treatment of mice with mg”loxpneo mutation of fibrillin-1 with the antioxidant lipoic acid (LA) induced aggravation of cardiovascular phenotype despite the inhibition of ERK. We postulate that LA induces a collateral pathway to ERK able to sustain the vascular phenotype. Understanding the way in which amplification AL modulates the phenotype of the disease despite the inhibition of ERK may provide alternative methods of treatment of disease. Published data suggest activation of the mTOR pathway by AL. Our hypothesis is that the path of mTORC1 complex may contribute to the phenotype of the SMF and potentially be a failure mechanism / reduction therapeutic response to the AT1 receptor inhibitors without exposure AL. The goal of the project is to investigate the profile of activation and expression of the mTORC1 complex and via ERK signaling in two major murine models of SMF (mg”loxpneo and C1039G). In these models, we will investigate the effect of treatment with rapamycin mTORC1 inhibitor in phenotype SMF cardiovascular (aorta / heart), and by histology and echocardiogram to assess the activity of matrix metalloproteinases. Moreover, VSMC isolated from SMF with C57BI6 mice, we will investigate the activation and expression induced AL mTORC1 complex mechanistic pathways and possible associated. These results may have significant translational implications. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MORETTI, ANA I. S.; PAVANELLI, JESSYCA C.; NOLASCO, PATRICIA; LEISEGANG, MATTHIAS S.; TANAKA, LEONARDO Y.; FERNANDES, CAROLINA G.; WOSNIAK, JR., JOAO; KAJIHARA, DANIELA; DIAS, MATHEUS H.; FERNANDES, DENISE C.; JO, HANJOONG; TRAN, NGOC-VINH; EBERSBERGER, INGO; BRANDES, RALF P.; BONATTO, DIEGO; LAURINDO, FRANCISCO R. M. Conserved Gene Microsynteny Unveils Functional Interaction Between Protein Disulfide Isomerase and Rho Guanine-Dissociation Inhibitor Families. SCIENTIFIC REPORTS, v. 7, DEC 8 2017. Web of Science Citations: 5.

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