Non-coding RNA and Intercellular Communication in Cardiac Ageing

Project Information

NICCA

Grant agreement ID: 101002599

DOI

10.3030/101002599

EC signature date 5 March 2021

Start date 1 April 2021

End date 31 March 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 999 690,00

EU contribution

€ 1 999 690,00

Coordinated by

STICHTING AMSTERDAM UMC
Netherlands

Periodic Reporting for period 3 - NICCA (Non-coding RNA and Intercellular Communication in Cardiac Ageing)

Reporting period: 2024-04-01 to 2025-09-30

Summary of the context and overall objectives of the project

Problem/Issue Being Addressed:
The project addresses the escalating challenge of age-induced cardiovascular disease, specifically focusing on heart failure with preserved ejection fraction (HFpEF). With life expectancy on the rise in the European Union, the prevalence of HFpEF is increasing concurrently. HFpEF is a complex condition involving various cellular mechanisms leading to impaired relaxation of cardiomyocytes. Currently, there is a lack of effective treatments for HFpEF, necessitating a deeper understanding of the molecular underpinnings of this condition.

Importance for Society:
This research holds importance for society due to the increasing burden of age-induced cardiovascular diseases, which pose a significant health risk, especially in an aging population. HFpEF, as a major clinical presentation of these diseases, has profound implications for the quality of life and healthcare resources. By comprehensively studying the molecular mechanisms associated with HFpEF, the project aims to contribute vital insights that can pave the way for innovative therapeutic strategies. Ultimately, the societal impact lies in the potential to mitigate age-induced cardiac dysfunction and improve the overall cardiovascular health of the aging population.

Overall Objectives:
The overarching objectives of the project are to unravel the molecular intricacies behind intercellular communication and aging that lead to HFpEF. Specifically, the project seeks to identify and characterize the role of long non-coding RNAs (lncRNAs), with a primary focus on Sarrah, in the context of cardiac aging and HFpEF. By conducting in-depth analyses of lncRNA involvement in cellular functions, the project aims to shed light on novel therapeutic targets to attenuate age-induced cardiac dysfunction. Moreover, the research endeavors to enhance our understanding of the underlying mechanisms controlling intercellular communication and cardiac function. Through these objectives, the project aims to contribute to advancements in the treatment and management of HFpEF, addressing a critical healthcare concern in an aging society.

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

As of the halfway point in the project, significant progress has been made in unraveling the molecular intricacies of age-induced cardiovascular disease, with a focus on heart failure with preserved ejection fraction (HFpEF), the most common type of heart failure in the elderly. The research has involved preliminary experiments that identified differentially regulated lncRNAs during cardiac aging, showcasing the importance of the cardiomyocyte-enriched lncRNA Sarrah in maintaining cardiomyocyte survival.

In the completed phase of the project, the team has undertaken extensive characterization of Sarrah's role in HFpEF and has begun the identification of other relevant lncRNAs associated with cardiac aging. Notably, the research has centered on those lncRNAs affected in a cohort of human HFpEF patients, providing a valuable bridge between experimental findings and clinical relevance.

The next phase of the project will build upon this foundation. The focus will shift towards a deeper understanding of the interplay between endothelial cells and cardiomyocytes in the context of both aging and HFpEF. Disturbed intercellular communication, identified as a hallmark of these conditions, will be further explored, and lncRNAs that regulate this crosstalk will be identified.

State-of-the-art in vitro and in vivo models will continue to be employed to assess cardiac aging and function. The upcoming experiments will involve manipulating the function of specific lncRNAs in a cell-type specific manner through gain-of-function and loss-of-function approaches. This step aims to provide a more comprehensive understanding of how these lncRNAs contribute to age-induced cardiac dysfunction and HFpEF.

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)

The researchers anticipate that the second half of the project will yield additional insights into the role of Sarrah and other lncRNAs in cardiac aging and HFpEF. This expanded knowledge is crucial in identifying novel therapeutic targets to mitigate age-induced cardiac dysfunction. Moreover, the research will contribute to advancing our understanding of the underlying mechanisms controlling intercellular communication and cardiac function, paving the way for potential breakthroughs in the treatment of HFpEF.