PROJECT II

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This project is focused on developing a "bottom-up" view of scalability across levels of biological organization from cells to tissue. For this we focus on how myocytes interact with one another to give rise to the electrical activities observed in heart muscle, particularly the pathological activities known as arrhythmias. The mechanical function of the heart is controlled by interactions between electrical and chemical signaling systems. In the simplest representation, electrical excitation in each heart cell leads to an increase in intracellular calcium concentration ([Ca2+]i), and contraction results from Ca2+ ions binding to myofilaments. However, changes in [Ca2+]i can influence the ionic currents responsible for excitation and thereby alter the electrical signal. Moreover, an optimal sequence of contraction at the organ level requires not only signaling within cells but also the effective transmission of signals between cells. Thus, the beating of the heart depends crucially on regulatory interactions and feedback loops, the common themes of the NYCSB. Because pathologies such as ischemia and heart failure are associated with disruptions in the coupling between electrical and Ca2+ signals, a better characterization of these loops at the cellular and tissue levels will improve our understanding of heart disease and suggest novel targets for therapies.