Kristin Ecke-=Mahan
Kristin Eckel-Mahan, PhD, studies circadian rhythms and the impacts of their disruptions.

During the time of the pandemic, there has been a constant — disruption. Disruptions in our daily routines, in our interactions with others, and to our sense of time.

Time is central not only to our organized lives but also to our organized bodies. Circadian (i.e. 24-hour) rhythms govern our wake-sleep cycles and responses to light and dark.

Kristin Eckel-Mahan, PhD, associate professor in the IMM’s Center for Metabolic and Degenerative Diseases, focuses her research on circadian rhythms and how their disruptions increase our risk for specific diseases or disorders.

“Historically, circadian rhythms were thought to be primarily controlled by the brain because part of the hypothalamus is directly responsive to light and dark. But the truth is that circadian rhythms occur at a cellular level and in almost all cells of the body. Rhythms occur at the level of gene expression and metabolic pathway activity at the cellular level.”

– Kristin Eckel-Mahan, PhD

People with disruption in their circadian clocks – such as those who work night shifts, or stay up too late – move their natural rhythm out of sync. This often involves an eating phase no longer coordinated with the light or active phase. Research shows those out of sync increase their risk of adverse cardiovascular events such as arrhythmias, obesity, and Type 2 diabetes.

Eckel-Mahan and her colleagues seek to understand other connections to disease and circadian disruptions, including connections with obesity and aging, gastric disorders, and cancer.

Working with colleague Mikhail Kolonin, PhD, Harry E. Bovay, Jr. Distinguished University Chair in Metabolic Disease Research, Eckel-Mahan is looking at the role of the circadian clock in fat tissue and its changes during a 24-hour cycle. “In this study, we are trying to understand how the circadian clock preserves a healthy fat pad throughout the aging of an organism,” she said, adding that they study tissue from gastric bypass surgery patients.

Studying the circadian clock’s role in gastrointestinal function, Eckel-Mahan is partnering with Rick Wetsel, PhD, Hans J. Muller-Eberhard, MD, PhD, and Irma Gigli, MD, Distinguished Chair in Immunology, in an investigation of the complement cascade — part of the body’s immune system. “Epidemiological studies show an increased incidence of irritable bowel disease and other gastrointestinal disorders that we think involves circadian disruptions of the complement cascade,” she said. “Some of these immune response pathways undergo 24-hour changes in activity, and depending on when you apply a toxin, you can get a different immune response.”

Timing treatments (often referred to as “chronotherapy”) also may produce different responses based on our internal circadian rhythms, Eckel-Mahan said. “The time of drug delivery may improve efficacy and reduce toxicity – this is at the forefront of all of our research,” she added.

Cancer is another area Eckel-Mahan and her colleagues are studying for clock connections. Working with scientists at MD Anderson Cancer Center, Eckel-Mahan is evaluating the circadian links associated with the natural flavonoid Nobiletin, a circadian modulating compound extensively investigated by Zheng (Jake) Chen, PhD, associate professor of Biochemistry and Molecular Biology, when applied to acute myeloid leukemia cells.

Her lab is also studying its effects in the context of hepatocellular carcinoma.

“We have administered this compound in vivo in mice and have seen accelerated cell death and delayed tumor progression in response.”

– Kristin Eckel-Mahan, PhD

Other ongoing work involves early stage liver disease, including non-alcoholic fatty liver disease, which is a direct result of the obesity epidemic and serves as a risk factor for developing fibrosis and hepatocellular carcinoma.

“We think that a high-fat diet decreases the expression of a tumor suppressor in the liver that has circadian activity. The result is circadian activation of proliferation genes that promote tumor formation and progression” she said.

Just one more reason to restore balance in our lives.


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