Grant: Project Grant

We live in a 24-hour world where our daily activities are organized around the day-night cycle. Many of us wake up, eat our meals, go to work, and sleep at approximately the same time every day. Our internal organs behave in a similar fashion, changing their activities over the course of 24 hours. These bodily rhythms, or so-called "circadian" rhythms, are the result of an internal clock in the brain, called the SCN (short for suprachiasmatic nucleus), that keeps track of the time of day and communicates that information to the rest of the body. However, many aspects of modern life are at odds with the workings of this internal timekeeping system. Rotating shift work, traveling across time zones and even "sleeping in" on weekends can lead to misalignment between our internal clock and the outside world. A misaligned or perturbed clock can have serious health consequences, such as increasing the risk of becoming overweight or developing diabetes, high blood pressure, heart disease, breast and prostate cancer, major depression, and Alzheimer's disease. Another major risk factor for many of these pathologies is aging, which is associated with a worsening in the performance of the SCN. By restoring or bolstering its performance and improving circadian rhythms, we may be able to treat or ameliorate various diseases, promote healthy aging, and enhance physical and mental health. The objective of this proposal is to identify and understand the genes responsible for the optimal performance of the SCN. We have found a gene called SOX2 that appears to be necessary for maintaining normal circadian rhythms. We will use various approaches, including mouse models where the Sox2 gene is "knocked out" in the SCN, to determine its roles in circadian timekeeping. Through our work, we will acquire new insights into how the SCN is regulated, knowledge that may be leveraged for the development of therapeutic and health-promoting strategies that target our internal clock.