Identifying novel networks of candidate Atrial Fibrillation genes in the Drosophila cardiac aging model

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Project Summary/Abstract Atrial fibrillation (AF), the most common heart rhythm disorder, is reaching epidemic proportions in the aging population, affecting nearly 33 million people worldwide. The incidence of AF increases with age, with individuals over the age of 65 having a 9% chance of developing this arrhythmia. AF is the leading cause of heart failure and stroke in human populations, and as the average lifespan continues to increase, so will the rates of these disorders. However, the molecular etiology of AF is not well defined and treatment options are limited. Additionally, there is evidence that common substrates link AF with other arrhythmia types and heart disease (e.g. long QT syndrome). Recent research has identified both common genetic variants that increase AF susceptibility in the general population and rare genetic variants linked to AF, suggesting that AF is likely a multifactorial disease whose etiology involves network(s) of interacting genetic variants. Resolving these complex interactions modulating cardiac function in AF is impractical in mammalian systems, but approachable using Drosophila genetics. Drosophila provide an advantage in unraveling the largely unknown genetic regulators of heart dysfunction due to the reduced genetic redundancy and high degree of conservation in the underlying pathways and cellular mechanisms. A subset of AF-associated candidate genes likely interact in a combinatorial manner with age and diet to cause cardiac arrhythmicity. Preliminary screens of candidate AF-related genes in both the fly heart and in human induced pluripotent stem cell atrial-like cardiomyocytes (hiPSC-ACMs) have identified a network of genes that suggests interactions between stearoyl-CoA desaturase (SCD) and two AF-associated genes, KCNA5 and phospholamban (PLN). SCD, a key lipid metabolic enzyme, is known to disrupt sarcoplasmic reticulum calcium ATPase pump (SERCA) activity, however, a KCNA5-SCD-SERCA-PLN network has not been well demonstrated in cardiac tissue. Cardiac phenotyping of interactions found in AF networks in both model systems will identify novel and likely conserved genetic pathways, providing novel therapeutic strategies. Sanford Burnham Prebys (SBP) is an environment that is highly supportive of research and collaborative interdisciplinary approaches, with extensive shared resources providing investigators with both cutting-edge equipment and technical expertise. Dr. Kezos has already mastered a number of complementary scientific concepts and approaches that he is using to address his research questions. Additionally, the Ocorr Laboratory is staffed with talented postdoctoral fellows and staff scientists who will be of assistance to Dr. Kezos during the research training. With the proposed training in the hiPSC model system, bioinformatics pipelines and CRISPR-Cas9 gene editing, Dr. Kezos will be well equipped to launch an impactful and independent research career to investigate the genetics of cardiomyopathies. The proposed research strategy and training plan will accelerate Dr. Kezos towards becoming an independent investigator with a research/teaching track position at a university.