Karen Ocorr, PhD - US grants

Summary 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.

Summary Atrial fibrillation affects 3-6 million people in the US. The risk of developing AFib and other cardiac arrhythmias increases with age. Individuals over the age of 65 have a 9% chance of developing AFib with an increased risk of stroke being the primary complication. Currently there are few options for treating AFib, primarily anticoagulation therapy to prevent blood clots and medications to control heart rate but there is no ?cure?. There is evidence that common substrates link AFib with other types of arrhythmia and heart disease. For example, the risk for AF is doubled in LQTS patients and the risk of TdP is much greater in patients with AF when taking ion channel blockers suggesting that AF has an influence on the QT interval. We hypothesize that homeostasis of the dynamic chromatin steady state (a process we have termed ?chromostasis?) of heart cardiomyocytes is critical for maintenance of an appropriate gene expression program, phenotype and function at the cellular and tissue levels over the life span. Using the Drosophila cardiac model, we will identify gene networks/cellular substrates for age-related arrhythmias based on age-dependent changes in transcriptomic signatures. We will first obtain functional data on hearts from young and old wildtype and arrhythmogenic K+ channel mutant flies. Because we anticipate that epigenetic ?drift? occurs over the lifespan and is manifest at several levels we will identify transcriptomics changes in individual hearts with manifest arrhythmia and between sub-regions of individual hearts that exhibit both normal and impaired function. Subsequent bioinformatics analyses will allow us to identify genetic networks that are associated with arrhythmic cardiac function. By comparing data from the wildtype and mutant fly lines at young and old ages, we will identify gene networks that are common to both types of arrhythmia. We will subsequently screen top candidate genes as well as genes previously identified in humans as being associated with AFib. The top hits from this screen will be examined for their ability to suppress arrhythmias in old hearts and in hearts with K+ channel mutations. Identification of the substrates for age-related arrhythmias will provide testable hypotheses that can be further explored to establish targets for therapeutic intervention.