MRNA IN HEART · mRNA translational regulation in heart failure
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2014-04-01 → 2016-08-29
- Финансиране от ЕС
- 187 415 €
- Участници
- 1
- Схема
- MC-IIF
Линиите свързват координатора с партньорите.
Накратко на български
Механизмите на протеиновия синтез в сърцето се анализират чрез проследяване на конкретни молекули (mRNA) при мишки с генетични промени. Това помага да се разбере как определени протеини регулират сърдечната функция и влияят върху развитието на сърдечна недостатъчност при стрес.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Periodic Report Summary 1 - MRNA IN HEART (mRNA translational regulation in heart failure)
The aim of our work was to determine the mechanisms through which mTOR and its targets 4E-BP1 and 2 regulate translation and thereby cardiac function. Using genetically recombinant mice, we have previously determined that the absence of mTOR in cardiac cells induce heart failure rapidly; this event could be partially but significantly prevented through the deletion of a target of mTOR, the inhibitor of translation 4E-BP1. Deleting both 4E-BP1 and 2, heart failure and mortality could be prevented even further. In addition, the sole deletion of 4E-BP1 and 2 could improve cardiac function during stress. These results indicated the necessity to determine the "translatome" that is, the mRNA associated with polysomes, in normal conditions and during stress, and determine which mRNA molecules are directly regulated by the inhibitors of translation 4E-BPs and which are influenced by mTOR itself. During this period of the study (six months), mRNA was collected from the myocardium of wild-type (WT) adult (2-month-old) sham-operated (sham) mice and from WT mice three days after transverse aortic constriction (TAC), a model in which blood pressure is greatly increased and myocardial stress induced. mRNA was also obtained from 4E-BP1-knock out (KO) mice before and three days after TAC. mRNA was also purified from ribosomes by immunoprecipitating them with an antibody specific for a protein component. cDNA libraries were generated and sequenced in our facility. Through this approach, we identified a pool of mRNAs which associated with ribosomes after stress and that therefore seems to be differentially regulated. In addition, we identified a pool of mRNAs which are regulated by 4E-BPs. These results should be confirmed by further analyses, which will be carried out by other investigators. Eventually, we should be able to identify mRNAs intimately related to the control of cardiac function, a result which will lead to a better understanding of the molecular mechanisms underlying heart failure and to new molecular tools which could be employed to combat this disease, which is one of the major health care burdens in the Western world.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.
Оригинален текст от CORDIS (на английски).
Участници
- HUMANITAS MIRASOLE SPA · Rozzano (Mi)КоординаторИталия
Връзки
Данни: CORDIS, © Европейски съюз