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Regenerative strategies for heart disease via targeting the long noncoding transcriptome

Applicant Pedrazzini Thierry
Number 173738
Funding scheme Sinergia
Research institution Département de Cardiologie CHUV
Institution of higher education University of Lausanne - LA
Main discipline Interdisciplinary
Start/End 01.10.2017 - 30.09.2022
Approved amount 2'793'733.00
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All Disciplines (3)

Discipline
Interdisciplinary
Molecular Biology
Cardiovascular Research

Keywords (10)

Long noncoding RNAs; Cardiomyocytes; Cardiac fibroblasts; Epigenome editing; Heart; Genome editing; Regeneration; Mouse models; High throughput screening; Reprogramming

Lay Summary (French)

Lead
Comment induire une régénération cardiaque, c’est-à-dire comment produire de nouvelles cellules musculaires cardiaques dans le cœur malade ? C’est la question que pose ce projet de recherche multidisciplinaire. La réponse se trouve peut-être dans un groupe de molécules régulatrices récemment identifiées : Les longs ARN non codants.
Lay summary

Les maladies cardiaques, en particulier l’infarctus du myocarde, représentent une cause majeure de mortalité dans les pays occidentaux. Le cœur humain contient environ 5 milliards de cellules musculaires, les cardiomyocytes, qui assurent la contraction quelque quatre-vingt fois par minute. Suite à un infarctus, le cœur perd un cinquième de ses cellules. Comment les remplacer ? Malheureusement, aucune thérapie actuelle n’est capable d’atteindre ce résultat. Il s’en suit une situation délétère dans laquelle le cœur compense le déficit de tissu musculaire par une cicatrice fibreuse qui contribue elle-même à exacerber la maladie et affecte gravement les chances de survie du patient à long terme.

Notre projet s’intéresse aux mécanismes qui permettent de produire des cardiomyocytes, pour remplacer notamment les cardiomyocytes morts après un infarctus du myocarde.  L’idée est donc de stimuler la régénération du cœur. Pour ce faire, nous allons cibler des molécules qui contrôlent l’identité des cellules : les longs ARN non codants. En contrôlant l’identité des cellules, on peut par exemple obliger des cellules à se multiplier. C’est le moyen le plus simple de produire des cardiomyocytes. L’autre approche se focalise sur un autre type de cellules cardiaques : les fibroblastes. Les fibroblastes produisent la cicatrice fibreuse dont nous avons parlé plus haut. Ce ne sont par contre pas des cellules contractiles et ne peuvent pas remplacer directement les cardiomyocytes. Cependant, si on contrôle l’identité de cellules, on peut tenter de transformer des fibroblastes en cardiomyocytes. Cette approche est possible en manipulant les longs ARN non codants.

Le projet implique quatre laboratoires, trois en Suisse et un en Italie, qui chacun apporte une expertise très particulière, indispensable au succès de l’entreprise. Cette collaboration amènera à une meilleure compréhension des longs ARN non codants et de la façon d’utiliser ces molécules pour développer de nouvelles thérapies.

Direct link to Lay Summary Last update: 25.09.2017

Responsible applicant and co-applicants

Employees

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Swiss Heart Foundation - Lausanne; Event for donators Western Switzerland 2019

Associated projects

Number Title Start Funding scheme
189877 Lnc-ing Cancer Drugs to Cardiotoxicity: Contribution of lncRNAs to Tyrosine Kinase Inhibitor-Related Cardiac Side Effects 01.06.2020 COST (European Cooperation in Science and Technology)
182322 Single-cell analysis of long noncoding RNA-mediated transcriptomic perturbations in cardiac fibroblasts 01.10.2018 Project funding
182337 The elements of long noncoding RNA function 01.03.2019 Project funding
201268 Analysis of the nucleolus and nucleolar chromatin factors in the regulation of genome architecture and function of stem cells 01.09.2021 Project funding
163476 Regenerative therapy for heart disease via modulation of long noncoding RNAs 01.10.2015 Project funding
173056 Analysis of nucleolus and nucleolar chromatin factors in the regulation of stem cells 01.05.2017 Project funding
152854 Role of nucleolar chromatin repressor TIP5 and non-coding RNA pRNA in the regulation of heterochromatin 01.05.2014 Project funding

Abstract

Coronary artery disease is the most frequent cardiovascular disorder in Western societies, and typically leads to acute myocardial infarction and ultimately heart failure. Heart failure is one of the major causes of morbidity and mortality. The human heart contains approximately 5 billion cardiomyocytes. An estimated 1 billion cardiomyocytes die after myocardial infarction. Despite the development of new pharmacological and device-based therapies, no approaches currently exist to compensate for the irreversible depletion of cardiomyocytes in the damaged heart. This results in accelerated myocyte death and deleterious development of fibrosis, a situation associated with very unfavorable prognosis. Heart failure is therefore evolving into a global epidemic, for which medicine has no viable option and is in need of rapid innovation. One area that has engendered considerable interest over the last decade is the premise of promoting cardiac regeneration.In this context, our project aims at identifying therapeutic molecules for stimulating regeneration in the mammalian heart. Intervention will target the most important populations in the heart, i.e. cardiomyocytes and cardiac fibroblasts. Regeneration will be achieved via direct cell reprogramming. Conceptually, cardiomyocytes will be reprogrammed into proliferating cells following dedifferentiation whereas cardiac fibroblasts will be reprogrammed into cardiac precursor cells and subsequently into cardiomyocytes. We will target a newly discovered layer of regulatory molecules, long noncoding RNAs (lncRNAs). LncRNAs can regulate gene expression both at the site of transcription, and at remote locations in the nucleus and cytoplasm, making them ideal regulators of epigenomic and post-transcriptional remodeling, which are key determinants of cellular reprogramming.The project is organized into specific aims. First, we will compare proliferating to non-proliferating cardiomyocytes, isolated from either the normal or the infarcted heart, to identify lncRNAs controlling cardiomyocyte proliferation. Second, we will compare adult cardiac fibroblasts to cardiac fibroblasts reprogrammed into induced cardiac precursor cells to identify lncRNAs controlling direct reprogramming into the cardiomyocyte fate. Epigenetic changes take place during developmental transitions in various cardiac lineages and during direct reprogramming. A characterization of the epigenetic landscape in each relevant population will therefore be performed. Then, bioinformatic analyses will be used to select candidate lncRNAs for cell-based high-throughput screening assays in vitro and in vivo. Finally, the efficacy of modulation of selected lncRNA expression in inducing heart regeneration will be tested in mouse models of myocardial infarction. The project is interdisciplinary in its nature since its success will depend on the application of a number of advanced technologies that exceed the potential competence of each individual laboratory. In this respect, the four involved laboratories show highly complementary, non-overlapping expertise. Ultimately, the project will benefit significantly in a synergistic manner from this collaboration, permitting achievement of results that ultimately would not be at reach for each of the individual laboratories.
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