Saturday, April 20, 2024
4/20/2024
PROJECT SUMMARY This grant proposes research on the molecular mechanisms that control the electrical activity of adult cardiac ventricular myocytes. Our focus is on the cardiac intercalated disc (ID), a region of the cell recognized as key to excitability and propagation and yet, only partly characterized in terms of its molecular composition, regulation and function. Our objective is to obtain a map of this structure by integrating proximity and visual proteomics, genomics, physiomics and molecule-specific physiology. We will study control hearts as well as those deficient in Plakophilin-2 (PKP2), an ID molecule that when mutated can cause lethal arrhythmias in the young. The ID was first described as an interdigitation of cell membranes at the site of end-end apposition between adult ventricular myocytes, hosting three electron-dense structures: gap junctions, desmosomes and adherens junctions (later redefined as mixed junctions or area composita1). More recent work shows that the ID also hosts protein complexes fundamental to electrophysiology. In fact, more than 70 years since it was described as an electron-dense structure, the ID emerges as a node that congregates the molecular machinery involved in all aspects of electrical activity: excitation, repolarization, propagation and control of Ca2+i. Despite the known importance of the ID in cell function, there is a wide knowledge gap regarding its molecular composition and its varied functional roles. Part of this limitation results from the fact that, as opposed to other membrane-wrapped cell components (e.g., mitochondria), isolation of the ID as a single organelle has not been possible given its complex geometry, and the fact that it is open to the cell interior without a limiting barrier of its own. Here, we circumvent these limitations by combining proximity and visual proteomics. The list of interactors will serve as a platform to query genomics and phenotype data, and to guide molecule-specific studies. Cardiac arrhythmias are common, debilitating and in many cases, fatal. Progress has been made in the development of devices and invasive strategies which, as sophisticated and life-saving as they are, can also cause serious and irreparable damage to the heart. In the context of medical therapy, the field of arrhythmias has been lagging behind others (e.g., cancer therapy), where a deep understanding of molecular components and their interdependence have led to the discovery of chemical agents that can slow down or arrest disease progression. We do not claim that our study can stop arrhythmias. But we do believe that knowledge of the molecular elements involved in rhythm control can lead to better risk assessment, diagnosis, prevention and therapy. The ID is a domain that concentrates multiple rhythm-control molecules and as such, a perfect target for applying proximity-based methods to advance our knowledge on the control of the heart rhythm.
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