Harnessing Novel Micropeptides in Cardiomyocytes to promote Cardiac Regeneration

Introduction

Despite advances in clinical care, heart failure consequent to myocardial infarction remains a leading cause of mortality worldwide. The absence of cardiac regeneration post-infarction is mostly explained by the reduced mitotic potential of adult cardiomyocytes. In comparison with their embryonic counterparts, adult cardiomyocytes have an accumulation of morphological, metabolic, and biochemical adaptations that render them recalcitrant to proliferation.

Objectives

Devising tools to precisely control the maturational status of cardiomyocytes would enable novel therapies for cardiac regeneration. This can be achieved by:

1. Stimulating cell cycle reentry of pre-existing cardiomyocytes.
2. Enhancing the maturational status of cardiomyocytes derived from induced pluripotent stem cells for cell therapy.

Research Focus

Novel.CaRe will explore the therapeutic potential of micropeptides, a novel class of proteins that, despite their small size, can play major cellular roles. Based on extensive preliminary work, I propose an ambitious interdisciplinary research program that bridges:

• Advanced omics
• Animal models
• Human samples
• Bioinformatics
• Cellular phenotyping
• Innovative strategies for gene therapy

Methodology

We will apply new translatomics and proteomics approaches to:

• Identify micropeptides conserved across species and modulated during cardiomyocyte maturation.
• Define their cellular functions.
• Test their potential to induce proliferation of cell cycle withdrawn cardiomyocytes or enhance maturation of stem cell-derived cardiomyocytes.

High-Risk, High-Gain Strategy

In a high-risk, high-gain part of the project, we will develop a novel approach for gene therapy. This will enable time-controlled, cardiomyocyte-specific expression of a combination of micropeptides normally expressed by embryonic cardiomyocytes. We will assess if this strategy successfully promotes regeneration of the adult heart post-injury.

Conclusion

In conclusion, Novel.CaRe will generate new resources, technology, and knowledge, pushing beyond the state-of-the-art in the fields of molecular cardiology and cardiac regeneration.