Unraveling pacemaker (dys)function using novel stem cell-derived human heart mod...
The pacemaker cells of the sinoatrial node (SAN) trigger three billion heartbeats in an average human life span. At the start of each beat, the SAN must generate enough current to drive the surrounding atrial tissue, which contain...
The pacemaker cells of the sinoatrial node (SAN) trigger three billion heartbeats in an average human life span. At the start of each beat, the SAN must generate enough current to drive the surrounding atrial tissue, which contains 10,000 times as many cells as the SAN itself. This extraordinary biological feat is a result of intrinsic features such as SAN tissue architecture. In addition, SAN function is modulated by extrinsic inputs from the autonomic nervous system, which adjusts the pace from beat-to-beat, for example during exercise. Any disturbances to these core activities result in SAN dysfunction, which include abnormal heart rate (brady or tachycardias), SAN exit block (lack of atrial activation) and chronotropic incompetence (inability to increase heart rate). SAN dysfunction is also a major trigger for atrial fibrillation, the most common form of arrhythmia.
The goal of this ERC-StG proposal is to make significant leaps in our understanding of the intrinsic and extrinsic factors that regulate SAN function in health and disease using innovative multi cell type as well as multi organ in vitro models created from human pluripotent stem cells. The first objective is to determine the role of SAN subpopulations, particularly transitional cells in facilitating impulse propagation at the pacemaker-atrial interface by evaluating an SCN5A loss-of-function mutation. The second objective is to gain insights into the relationship between SAN-dysfunction and atrial fibrillation by assessing MYH6 variants associated with both these diseases. Lastly, the third objective will unravel how damage to autonomic function in the higher orders of the brain, for e.g., in neurodegenerative diseases such as Huntington’s disrupts electrical activity of pacemaker cells. This research will provide exquisite knowledge of the fundamental principles that regulate pacemaker function which is essential to effectively address SAN dysfunction and atrial arrhythmias.ver más
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