175 Oral - Models of Human Disease II
Saturday April 09, 10:45 AM - 11:00 AM

Authors:
Farah Abou Daya ¹; Torrey Mandigo ^2,4; Shubhroz Gill ^2,4; James Walker ^2,4; Richa Saxena ^2,3,4; Girish Melkani ¹

Affiliations:
1) Division of Molecular and Cellular Pathology, Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 2) Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; 3) Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 4) Broad Institute, Cambridge, MA, USA

Keywords:
j. cardiovascular disease; k. circadian rhythms and sleep

Insomnia is a common disorder defined by constant difficulty in falling and/or staying asleep. Studies have shown that insomnia is associated with cardiovascular disease (CVD) where insomnia confers more than a 2-fold increased risk of incident CVD. However, the specific shared causal pathways remain poorly understood, making it difficult to identify new therapeutic targets for insomnia that ameliorate CVD risks. Recently, our collaborators found 57 genome-wide significant genetic loci for insomnia. To identify causal genes under these association peaks and understand the mechanisms linking insomnia with CVD, we use Drosophila melanogaster models, which are well-established model systems for sleep and cardiac studies. We hypothesized that suppressing Drosophila orthologs of causal human insomnia genes will lead to compromised sleep and cardiac function. To assess the role of genes associated with the identified loci on cardio-physiology, we obtained RNAi stocks of 72 orthologs of genes under the 57 human genetic association peaks. Knockdown (KD) of these genes was done using the cardiac-specific Hand-Gal4 driver. 1-week-old Drosophila progeny were then used for semi-intact microscopic heart preparation followed by high-speed videography to assess cardiac physiological parameters. Similarly, to assess their role in sleep, KD of these genes was done using the neuron-specific ELAV-Gal4 driver. Sleep and locomotor activity of 3 to 7-day-old flies was monitored using the Drosophila Activity Monitoring System. Interestingly, our initial results show that 3 of 4 genes with fly orthologs, ATPSynC, Bruce and Larsen, within one insomnia genetic locus, show sleep and cardiovascular phenotypes. Mainly, cardiac-specific KD of Larsen led to significant cardiac dilation and reduced cardiac performance, while KD of Bruce led to significantly reduced cardiac performance without significant dilations. Moreover, KD of ATPSynC led to a compromised beating pattern with an elongated diastolic interval and shortened life span. Additionally, neuronal-specific KD of all 3 genes led to sleep fragmentation with only Larsen resulting in a significant decrease in overall sleep which was primarily due to a decrease in nighttime sleep. Assessments of inter organ crosstalk for this locus and measurements of sleep and cardiac parameters of other genetic lines are still in progress. This work will reveal mechanisms linking insomnia and CVD which would help prevent and treat both diseases.