Grants and Contracts Details


The importance of the rapidly activating delayed rectifier K+ current (IKr) for electrical stability in the heart is clear. Long QT syndrome (LQTS) is a life-threatening arrhythmogenic condition that is caused by drugs or mutations that decrease IKr. For nearly 20 years investigators have studied the pharmacological sensitivity of IKr, and they have characterized hundreds of different disease-causing mutations in Kcnh2, the gene that encodes the IKr channel á-subunit Kv11.1. The goal of this project is to provide mechanistic insight for the transcriptional regulation of Kcnh2. We expect that this work will provide the foundation for novel therapeutic strategies that increase the functional expression of Kcnh2 to effectively prevent life-threatening arrhythmias caused by LQTS. To achieve this goal, the following aims are pursued: Aim 1. Bmal1 and Clock1 Regulate the Circadian expression of Kcnh2 transcripts and contribute to the steady-state levels of Kv11.1 channels in the cell surface. • Identify conserved promoter elements that control the circadian expression of human Kcnh2. • Demonstrate that core circadian transcription factors Bmal1 and Clock regulate Kcnh2 mRNA expression, Kv11.1 protein levels, and IKr in cardiomyocytes. Aim 2. Animal models of chronic jet lag or circadian desynchrony disrupt Bmal1 and Clock signaling in the heart to suppress the transcriptional and functional expression of Kcnh2. • Confirm the circadian regulation of Kcnh2 by Bmal1 and Clock in vivo. • Demonstrate Bmal1 and Clock binding to the Kcnh2 promoter increases nascent Kcnh2 mRNA. • Demonstrate that chronic jet lag or circadian desynchrony negatively impact Bmal1 and Clock signaling in the heart to suppress the functional expression of Kcnh2.
Effective start/end date3/8/192/28/24


  • National Heart Lung and Blood Institute: $2,310,512.00


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