Objective
Protein synthesis is among the principal biological processes underlying cardiac hypertrophy, an early event in many forms of heart failure (HF). It is associated with worsening of cardiac function after long-term exposure to noxae. The rate-limiting step of protein synthesis is mRNA translation, which is controlled by factors involved in initiation and/or elongation. 4E-BPs regulate the translation of a subset of mRNAs by competing with eIF4G for binding to eIF4E, preventing the assembly of eIF4F and hence inhibiting translation. The overall aim of this project is to determine the role of the Eif4E-binding proteins in protein synthesis in the cardiomyocyte, identifying 4E-BP-regulated mRNAs that mediate cardiac function in normal and disease states.
We recently generated a cardiac-specific mTOR-/- mouse line and found that it develops rapid cardiac dilation and impaired heart function without undergoing an initial hypertrophic phase; mortality reached 100% within 8 weeks of inducing the deletion with tamoxifen (TMX). A striking feature of this HF model is the accumulation of the dephosphorylated (active) form of the mTOR substrate 4E-BP1 within the myocardium. We noticed that this occurs also in other models of HF, including embryonic mTOR-/- heart, pressure-overloaded wild-type (WT) mice, raptor-/- mice, and MLP-/- mice. When mTOR-/- mice were crossed with 4E-BP1-/- mice, 4E-BP1 accumulation was abolished, cardiac function was ameliorated, and survival was significantly, albeit only partially, improved. Therefore, we hypothesized that elevated dephosphorylated 4E-BP is linked to heart failure through translational inhibition of a subset of mTOR-activated mRNAs. This project will add new, significant information on the regulation of gene expression in compensatory hypertrophy after stress and on the pathophysiology of myocardial hypertrophy and failure.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- social sciences sociology demography mortality
- medical and health sciences basic medicine physiology pathophysiology
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences clinical medicine cardiology
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2013-IIF
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
20100 Rozzano (Mi)
Italy
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.