Heart failure represents a growing global health burden, significantly impacting patient quality of life and healthcare systems. A prominent form, heart failure with preserved ejection fraction (HFpEF), remains poorly understood, lacking effective therapeutic options. Central to heart function is the sarcomere, the basic unit responsible for heart contraction, where the giant protein titin plays a critical role. Titin not only influences muscle elasticity but also participates in sensing mechanical stress, signaling to the nucleus, and subsequently affecting gene expression through a process known as mechanotransduction.
The MERAS project (Mechanoregulation of Alternative Splicing) investigates how mechanical signals from the heart muscle affect the alternative splicing of genes—an essential regulatory mechanism that allows a single gene to generate multiple protein variants. Misregulation of alternative splicing significantly contributes to cardiac diseases. MERAS utilizes state-of-the-art multi-omics approaches, combining advanced proteomics, transcriptomics, and single-cell sequencing to unravel the mechanistic links between mechanical stress and splicing regulation.
The overall goal of MERAS is to map how mechanical forces within cardiac muscle cells regulate alternative splicing, and identify how disruptions in these pathways contribute to heart disease. The project employs engineered heart tissues (EHTs) derived from human induced pluripotent stem cells (hiPSCs), allowing precise control of mechanical and environmental conditions.
By integrating machine learning techniques for data analysis, MERAS researchers can identify patterns and interactions within extensive datasets, significantly enhancing the understanding of cardiac mechanotransduction. Such insights are crucial for developing targeted therapeutic strategies.
Ultimately, MERAS aims to translate foundational biological discoveries into clinical innovations. The identification of new molecular targets and mechanisms promises to guide future drug development, addressing a critical need in cardiology. By bridging basic science and clinical application, MERAS aims to improve our ability to manage and treat heart failure and enhance patient outcomes.
