Cardiac performance significantly impacts quality of life; cardiac dysfunction and arrhythmia increase with age and can lead to heart disease, the number one cause of death in the United States. Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and AF significantly increases the risk of heart failure and stroke. A genetic basis for AF is indicated in one third of patients and pro-fibrotic and apoptotic effects of sustained AF in patients and animal models have been documented. A major barrier to understanding the interplay between electrical and structural cardiac remodeling is the overwhelming complexity of mammalian systems. In order to define fundamental molecular/genetic links, I propose to use a simpler, genetically tractable model, Drosophila. The fruit fly has proven extremely useful in elucidating the first conserved genetic networks responsible for heart development and in identifying cellular mechanisms underlying adult heart function and disease. I have identified important similarities in ion channel function and cardiac arrhythmias between flies and humans including early afterdepolarizations that lead to tachyarrhythmias. Genetic analyses of hearts from flies with mutations in these channels reveal interesting differences in wnt and hippo signaling pathways and suggest possible connections between them. Individually, these pathways have been implicated in human heart cardiomyopathies and there are tantalizing suggestions that these pathways may be involved in maintenance and regeneration of adult cardiac function. I will use the fly cardiac model I have developed to elucidate underlying genetic/molecular connections between these pathways in both ?healthy? and ?diseased? hearts with subsequent validation in the vertebrate zebrafish heart model. The interplay between electrical activity, Ca2+ handling, and cardiac function/structure is likely a balancing act for post-mitotic organs with limited regenerative capacity; understanding this will be important in developing effective therapies to treat human cardiomyopathies.
Atrial fibrillation, the most common form of cardiac arrhythmia, can lead to electrical and structural remodeling of the heart with often fatal outcomes. I propose to use the Drosophila and zebrafish models to identify and validate genes that mediate the effects of tachyarrhythmias and contribute to cardiac remodeling in disease. Understanding the role of these pathways and their interactions in the heart will likely identify novel therapeutic targets and shed light on the regulation of cardiac regeneration.
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