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Regenerative therapy for heart disease via modulation of long noncoding RNAs

English title Regenerative therapy for heart disease via modulation of long noncoding RNAs
Applicant Pedrazzini Thierry
Number 163476
Funding scheme Project funding
Research institution Département de Médecine CHUV
Institution of higher education University of Lausanne - LA
Main discipline Cardiovascular Research
Start/End 01.10.2015 - 30.09.2018
Approved amount 525'000.00
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Keywords (7)

Transgenic mice; Human; Regeneration; Heart; Enhancer; Long noncoding RNAs; Physiology

Lay Summary (French)

Lead
Les maladies cardiovasculaires représentent une cause majeure de mortalité. L’infarctus du myocarde et l’insuffisance cardiaque atteignent dans les pays développés des niveaux alarmants. Malgré le développement de nouvelles thérapies, la seule option thérapeutique de l’insuffisance cardiaque est la transplantation cardiaque. Cependant, celle-ci est limitée en raison du manque de donneurs. La médecine est donc en nécessité d’innovation rapide. Un domaine qui engendre un intérêt considérable est la possibilité d’induire une régénération tissulaire du cœur endommagé. Les cardiomyocytes, les cellules musculaires du cœur, pourrait être reprogrammé pour les forcer à se diviser. Par ailleurs, les précurseurs cellulaires dans le cœur pourraient manipulés de façon à les obliger à produire des cardiomyocytes. En d’autres termes, le cœur a besoin de produire du muscle après un infarctus et la source de cardiomyocytes peut être soit les cardiomyocytes eux-mêmes soit des précurseurs cardiaques.
Lay summary

La programmation cellulaire ou différenciation et la reprogrammation ou changement de comportement cellulaire dans les tissus sont sous contrôle de mécanismes moléculaires impliquant de nombreux régulateurs mais il est devenu évident au cours des dernières années que les mécanismes contrôlés par les ARN non codants sont particulièrement importants.

Que sont les ARN non codants ? Dans le génome humain, les gènes qui codent pour des protéines sont appelés des gènes codants. Ces gènes codants sont très importants mais ne représentent que 2% du génome. The 98% restants sont appelés le génome non codant. Le fait que cette portion du génome ne code pas pour des protéines ne signifie aucunement qu’elle ne puisse pas produire de l’ARN. En effet, de l’ARN non codant est transcrit à partir du génome non codant. De plus, ces ARN non codants ont d’importantes fonctions comme régulateurs de l’expression des gènes codants, et par là même des la programmation et de la reprogrammation cellulaires.

Dans ce projet, notre objectif principal est dès lors d’identifier les ARN non codants qui régulent la prolifération des cardiomyocytes ou la différenciation des précurseurs cardiaques. Une fois identifiés, ces molécules pourront être ciblées dans le cœur et leur potentiel thérapeutique in vivo à induire une régénération cardiaque pourra être testé dans des modèles d’infarctus du myocarde.

Direct link to Lay Summary Last update: 28.09.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Les longs ARN non codants dans le système cardiovasculaire : futures cibles thérapeutiques
Pedrazzini T. (2018), Les longs ARN non codants dans le système cardiovasculaire : futures cibles thérapeutiques, in Archives des Maladies du Coeur et des Vaisseaux - Pratique, 2018(272), 16-20.
A transcribed enhancer dictates mesendoderm specification in pluripotency
Alexanian Michael, Maric Daniel, Jenkinson Stephen P., Mina Marco, Friedman Clayton E., Ting Ching-Chia, Micheletti Rudi, Plaisance Isabelle, Nemir Mohamed, Maison Damien, Kernen Jasmin, Pezzuto Iole, Villeneuve Dominic, Burdet Frédéric, Ibberson Mark, Leib Stephen L., Palpant Nathan J., Hernandez Nouria, Ounzain Samir, Pedrazzini Thierry (2017), A transcribed enhancer dictates mesendoderm specification in pluripotency, in Nature Communications, 8(1), 1806-1806.
The long noncoding RNA Wisper controls cardiac fibrosis and remodeling
Micheletti Rudi, Plaisance Isabelle, Abraham Brian J., Sarre Alexandre, Ting Ching-Chia, Alexanian Michael, Maric Daniel, Maison Damien, Nemir Mohamed, Young Richard A., Schroen Blanche, González Arantxa, Ounzain Samir, Pedrazzini Thierry (2017), The long noncoding RNA Wisper controls cardiac fibrosis and remodeling, in Science Translational Medicine, 9(395), eaai9118-eaai9118.
New Lncs to mesendoderm specification
Alexanian Michael, Pedrazzini Thierry, Ounzain Samir (2017), New Lncs to mesendoderm specification, in Journal of Thoracic Disease, 9(S1), S5-S8.
Cardiomyocyte Lineage Specification in Adult Human Cardiac Precursor Cells Via Modulation of Enhancer-Associated Long Noncoding RNA Expression
Plaisance Isabelle, Perruchoud Stéphanie, Fernandez-Tenorio Miguel, Gonzales Christine, Ounzain Samir, Ruchat Patrick, Nemir Mohamed, Niggli Ernst, Pedrazzini Thierry (2016), Cardiomyocyte Lineage Specification in Adult Human Cardiac Precursor Cells Via Modulation of Enhancer-Associated Long Noncoding RNA Expression, in JACC: Basic to Translational Science, 1(6), 472-493.
Long non-coding RNAs in heart failure: a promising future with much to learn
Ounzain Samir, Pedrazzini Thierry (2016), Long non-coding RNAs in heart failure: a promising future with much to learn, in Annals of Translational Medicine, 4(15), 298-298.
Super-enhancer lnc s to cardiovascular development and disease
Ounzain Samir, Pedrazzini Thierry (2016), Super-enhancer lnc s to cardiovascular development and disease, in Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1863(7), 1953-1960.
Divergent Paths Lnc Cell Fates
Ounzain Samir, Pedrazzini Thierry (2016), Divergent Paths Lnc Cell Fates, in Cell Stem Cell, 18(5), 561-562.
Comparative transcriptome profiling of the injured zebrafish and mouse hearts identifies miRNA-dependent repair pathways
Crippa Stefania, Nemir Mohamed, Ounzain Samir, Ibberson Mark, Berthonneche Corinne, Sarre Alexandre, Boisset Gaëlle, Maison Damien, Harshman Keith, Xenarios Ioannis, Diviani Dario, Schorderet Daniel, Pedrazzini Thierry (2016), Comparative transcriptome profiling of the injured zebrafish and mouse hearts identifies miRNA-dependent repair pathways, in Cardiovascular Research, 110(1), 73-84.
Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy
Shende Pankaj, Xu Lifen, Morandi Christian, Pentassuglia Laura, Heim Philippe, Lebboukh Sonia, Berthonneche Corinne, Pedrazzini Thierry, Kaufmann Beat A., Hall Michael N., Rüegg Markus A., Brink Marijke (2015), Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy, in Cardiovascular Research, 109(1), 103-114.
CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis
Ounzain Samir, Micheletti Rudi, Arnan Carme, Plaisance Isabelle, Cecchi Dario, Schroen Blanche, Reverter Ferran, Alexanian Michael, Gonzales Christine, Ng Shi Yan, Bussotti Giovanni, Pezzuto Iole, Notredame Cedric, Heymans Stephane, Guigó Roderic, Johnson Rory, Pedrazzini Thierry (2015), CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis, in Journal of Molecular and Cellular Cardiology, 89, 98-112.
Discovery and functional characterization of cardiovascular long noncoding RNAs
Ounzain Samir, Burdet Frédéric, Ibberson Mark, Pedrazzini Thierry (2015), Discovery and functional characterization of cardiovascular long noncoding RNAs, in Journal of Molecular and Cellular Cardiology, 89, 17-26.

Collaboration

Group / person Country
Types of collaboration
Prof. Mauro Giacca; ICGEB, Trieste, Italy Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Ioannis Xenarios, SIB, Lausanne, Switzerland Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

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)
130505 A systematic and functional analysis of HIF-dependent splice regulator expression and pre-mRNA alternative splicing in pathologic stress-induced cardiac hypertrophy 01.01.2011 Sinergia
173738 Regenerative strategies for heart disease via targeting the long noncoding transcriptome 01.10.2017 Sinergia
127590 Importance of the Notch pathway in cardiac tissue homeostasis 01.10.2009 Project funding
128129 Identification of miRNAs modulating the regenerative response of the heart in the zebrafish and the mouse 01.06.2010 NRP 63 Stem cells and regenerative medicine
182322 Single-cell analysis of long noncoding RNA-mediated transcriptomic perturbations in cardiac fibroblasts 01.10.2018 Project funding

Abstract

In the Western world, cardiovascular diseases represent a major cause of mortality and morbidity. Heart failure in particular is evolving into a global epidemic. Despite the development of new therapies, no approaches currently exist to reverse the loss of cardiomyocytes in the failing heart. The only option for end-stage heart failure remains heart transplantation, which is limited due to the increased demand and scarcity of donor hearts. Medicine is therefore in need of rapid innovation. In this context, one area that has engendered considerable interest over the last decade is the premise of inducing regeneration in the damaged heart. Cardiac myocytes could be reprogrammed in situ to reenter the cell cycle. In addition, cardiac precursor cells could be manipulated to favor conversion into functional cardiomyocytes. Both strategies aim at producing newly formed cardiomyocytes.Long noncoding RNAs (lncRNAs) represent a class of RNAs with no apparent protein-coding potential. LncRNAs are emerging as master regulators of gene expression. LncRNAs appear to function during development to repress non-appropriate gene networks through the recruitment of repressive chromatin modifying complexes. In addition, lncRNAs, which are transcribed from active enhancer sequences (enhancer-associated lncRNAs), contribute to neighboring gene activation via cis-mechanisms.In the heart, lncRNAs are emerging as key regulators of programming and reprogramming of cardiac cells during development and in adulthood. In a first study, we have used very deep RNA sequencing to profile the noncoding transcriptome in the mouse heart after myocardial infarction. We have identified 1500 novel lncRNAs via RNA Seq and ab initio reconstruction. We also integrated publically available genome-wide data sets to functionally characterize lncRNAs and associate them with specific cardiac pathological processes. The vast majority of newly discovered heart-specific lncRNAs were predominantly derived from enhancer sequences. More recently, we have applied this strategy to analysis various lncRNA transcriptomes in mouse embryonic stem cells or human cardiac precursor cells differentiating into cardiomyocytes. We have therefore generated several catalogs of novel lncRNAs, which contains hundreds of candidates and can be screened for identifying lncRNAs demonstrating functional importance during cardiac cell programming and reprogramming.Our main objective is therefore to identify lncRNAs from our catalogs, which could be targeted to induce adult mouse cardiomyocyte proliferation and/or cardiogenic differentiation in human cardiac precursor cells. We will first bioinformatically preselect candidates from the lncRNA catalogs based on predicted function in relevant biological situations. We will next design modified antisense oligonucleotide inhibitors (GapmeRs) to specifically target the selected lncRNAs. GapmeRs will be systematically evaluated for their capacity to induce reprogramming in high throughput functional assays. We propose to deplete lncRNAs to alleviate repression of particular states, and facilitate reprogramming. Therapeutic depletion of candidate lncRNAs is indeed desirable for both biological and technical reasons. In addition, because of the stringent selection of candidate lncRNAs, GapmeR-based therapies will target only highly cell-specific lncRNAs. Off-target effects are de facto excluded because no cell types are expected to express the targeted lncRNAs, making these therapeutic agents ideal for translation in the clinic. Thus, experiments will be designed to validate in vivo findings obtained from functional screens performed in vitro, and evaluate the capacity of identified GapmeRs to induce regeneration in the adult heart.
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