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ERC

LONGHEART Report Summary

Project ID: 648038
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - LONGHEART (Exploring selected long non-coding RNAs as diagnostics and therapeutic targets for heart failure)

Reporting period: 2015-06-01 to 2016-11-30

Summary of the context and overall objectives of the project

Cardiac stress such as myocardial infarction or hypertension leads to cellular “remodeling” of the left ventricle resulting in heart failure. Protein-coding genes originate from only 1.5% of the genome, whereas the larger remaining portion is often transcribed to non-coding RNAs, of which functional importance is still ill understood. We pioneered a role of small microRNAs as diagnostics and therapeutic targets for heart failure (Nature, 2008; Nature Comm, 2012, J Clin Invest, 2014). We now will focus on the larger fraction of long non-coding RNAs (lncRNAs) and their functional roles, as well as diagnostic and therapeutic use in heart failure.
Despite clinical advances, diseases of the cardiovascular system are the most common cause of morbidity and mortality in the EU with currently 50 million people suffering from heart failure. These important challenges call for a better understanding of underlying mechanisms to enable development of innovative, effective diagnostic and therapeutic strategies for heart failure.
The proposal has the following interconnected objectives: a) identify novel functional relevant cardiac remodeling-associated lncRNAs; b) characterise key lncRNA cardiac targetomes; c) investigate lncRNA-paracrine mechanisms and the diagnostic and prognostic potential of cardiac-derived extracellular lncRNAs using large clinical cohorts; and d) discover their therapeutic potential to prevent cardiac remodeling in clinically relevant animal models. Innovative molecular and cell-based methods, a unique lncRNA-shRNA library, genetic animal models and availability of large clinical biobanks will form the basis for a successful strategy. LONGHEART will lead to ground-breaking new insight into the role of lncRNAs in the heart. These findings will firmly establish lncRNA-based mechanisms to identify fundamentally novel diagnostic and therapeutic entry points for a most serious clinical important disorder in dire need for new diagnostic and therapeutic paradigms.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Within LONGHEART we are within our timelines, personal has been successfully recruited and we do not see any problems for delays or other problems.
We have started to focus on the large fraction of long non-coding RNAs (lncRNAs) and their functional roles, as well as diagnostic and therapeutic use in heart failure. The proposal has the following interconnected objectives and I will briefly describe the current status of our work
a) identify novel functional relevant cardiac remodeling-associated lncRNAs;
Status: We have implemented novel high-throughput methods for lncRNA identification and already identified and patented several lncRNA candidates as interesting novel therapeutic targets. For instance, by using global lncRNA expression profiling we found several lncRNA transcripts to be deregulated during pressure overload-induced cardiac hypertrophy in mice. Using stringent selection criteria, we identified Chast (cardiac hypertrophy-associated transcript) as a potential lncRNA candidate that influences cardiomyocyte hypertrophy. Cell fractionation experiments indicated that Chast is specifically up-regulated in cardiomyocytes in vivo in transverse aortic constriction (TAC)-operated mice. In accordance, CHAST homolog in humans was significantly up-regulated in hypertrophic heart tissue from aortic stenosis patients and in human embryonic stem cell-derived cardiomyocytes upon hypertrophic stimuli. Viral-based overexpression of Chast was sufficient to induce cardiomyocyte hypertrophy in vitro and in vivo. GapmeR-mediated silencing of Chast both prevented and attenuated TAC-induced pathological cardiac remodeling with no early signs on toxicological side effects. Mechanistically, Chast negatively regulated Pleckstrin homology domain-containing protein family M member 1 (opposite strand of Chast), impeding cardiomyocyte autophagy and driving hypertrophy. These results indicate that Chast can be a potential target to prevent cardiac remodeling and highlight a general role of lncRNAs in heart diseases. This study has been recently published in the prestigious journal Science Translational Medicine (Viereck et al., Science Transl Med. 2016 Feb 17;8(326):326ra22. doi: 10.1126/scitranslmed.aaf1475). In addition, a set of further lncRNAs have been identified that are currently under investigation within LONGHEART.
b) characterise key lncRNA cardiac targetomes;
Status: We have started to use lncRNA-pulldowns to study lncRNA/protein interactions. First data have been already published (Viereck et al., Science Transl Med. 2016 Feb 17;8(326):326ra22. doi: 10.1126/scitranslmed.aaf1475).
c) investigate lncRNA-paracrine mechanisms and the diagnostic and prognostic potential of cardiac-derived extracellular lncRNAs using large clinical cohorts;
Status: We have started to discover lncRNAs secreted by hypoxic cardiomyocytes and results will be presented in a Keystone meeting (March 2017), which I am organizing (Keystone, Colorado. USA).
d) discover their therapeutic potential to prevent cardiac remodeling in clinically relevant animal models.
Status: We have developed AAV-based cell type specific targeting vectors for the modulation of cardiac lncRNAs and have provided first evidence for therapeutic manipulation of lncRNAs in heart diseases (Viereck et al., Science Transl Med. 2016 Feb 17;8(326):326ra22. doi: 10.1126/scitranslmed.aaf1475). Further studies are ongoing.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We have made several public press releases to increase awareness about our research funded by the EU (e.g. https://www.mh-hannover.de/46.html?&L=1&tx_ttnews%5Btt_news%5D=4404&cHash=c1ed2f654cc3975e60ae2a477db165cd)
In addition, Prof. Thum organized an upcoming Keystone meeting (March 2017), where EU-Longheart funded projects will be presented.
Record Number: 198062 / Last updated on: 2017-05-16
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