Dakup conducted the experiments for the study as part of a predoctoral fellowship supported by the American Heart Association. Additional major support for the study came from the National Institutes of Health.
In the study's main experiment, Dakup looked at the heart function of two groups of mice with disrupted clocks, as compared to that of control mice. One group had a genetic mutation that eliminated Per1 and Per2--two genes that control the body's master biological clock. The second group were wild-type mice that were put on a simulated rotating shift schedule in which light-dark cycles were reversed weekly, throwing off their clocks. The control group consisted of wild-type mice with healthy biological clocks that were on a simulated day shift schedule. All mice received radiation treatment to the chest that included all of the heart.
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Collaborating with assistant professor of pharmaceutical sciences and cardiovascular biology expert Zhaokang Cheng, Dakup used ultrasound echocardiography technology to compare heart function among the three groups, both prior to and up to six weeks after radiation treatment. In clock-disrupted mice, the heart's ability to pump blood out and into circulation was compromised due to a loss of elasticity in the heart ventricle. Those mice also had more heart scar tissue than control mice.
Additional analyses focused on determining a potential relationship with the biological clock protein Bmal1. The researchers showed that Bmal1 levels across 24 hours were significantly lower in clock-disrupted mice versus control mice and peaked at a later time. They also found that higher levels of Bmal1 were associated with lower DNA damage levels, and vice versa.
Finally, the researchers found that Bmal1 interacts with the BRCA1, BRCA2, and ATM genes, three DNA damage response genes they said are important in fighting against radiation-induced DNA damage and cell death.
"When Bmal1 binds to these genes, it is potentially trying to elevate or activate their function against the collateral damage caused by radiation therapy," Gaddameedhi said.
The researchers' next step is to test their hypothesis in a cancer model. This will help them pin down the exact mechanism by which the biological clock protects the heart from radiation damage. They could then use this knowledge to develop new treatment strategies to minimize heart damage while maximizing the ability to kill tumor cells. Any such strategies would first need to be tested in clinical trials before they could be adopted.