Transcriptional Regulation of KCNH2

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Summary Circadian rhythms help to match the optimal function of the cardiovascular system to the daily changes in the environment. Normal cardiovascular rhythms provide a physiological advantage to people. Unfortunately, normal circadian signaling can also unmask a time-of-day pattern in adverse events like heart attack, stroke, and sudden death in patients with underlying cardiovascular disease. Emerging data now show that abnormal or unhealthy daily rhythms can create a negative impact on normal health too. For example shiftwork, which repeatedly causes shifts in endogenous circadian rhythms, is an independent risk factor for cardiovascular disease. In mammals the suprachiasmatic nucleus (SCN) in the brain is the primary circadian pacemaker that helps to entrain endogenous rhythms to the environment. SCN rhythms are synchronized to the environment via light, and its signaling helps to coordinate the molecular rhythms in cells throughout the body. What is new about this application is we determine how repeated changes in light cycle will impact molecular circadian signaling in the heart. Most cells have a molecular clock signaling mechanism that cycles with a periodicity of ~24 hours. We found genetic disruptions in the molecular clock mechanism of heart cells (cardiomyocytes) primarily causes abnormal changes in cardiac electrophysiology by disrupting the regulation of ion channel function. The goal of this application is to determine how repeated shifts in the light cycle impact molecular clock signaling in the mouse heart and its regulation on ion channel function. Aim 1. To identify new mechanisms with which the cardiac molecular clock regulates different ion channels. Aim 2. To determine how repeated changes in light impact molecular clock signaling in the heart and ion channel regulation. This project creates new knowledge at the interface between chronobiology and cardiac electrophysiology.