Common threads

Posted on: 8/12/2014; Updated on: 8/12/2014
By Steven Powell, 803-777-1923

Heart attack, stroke and cancer—three distinct afflictions. But a discerning eye can see the connections, the commonalities that link the illnesses. The School of Medicine's Daping Fan has that kind of vision.

Together, heart attack and stroke account for one-third of all U.S. deaths. The common culprit in both cases is plaque buildup in the blood vessels, sometimes called hardening of the arteries. Plaques usually grow gradually, slowly lining the vessel and squeezing off the space that blood needs to freely flow through the arteries. The process can eventually cause symptoms such as shortness of breath, chest pain, and fainting, a sign that atherosclerosis has set in and must be medically addressed.

But plaque can also cause sudden, unexpected problems as well. Subjected to the physical forces of blood flow, fragments can break free, exposing the plaque's core, which is likely to cause a clot that can restrict or even completely block blood flow. The fragments, too, are trouble. They might travel through the bloodstream, lodge in a new location, and form a clot there having the same risks.

One goal of Fan's research is to develop strategies to slow down plaque growth. Plaques grow when lipids – fats traveling through the bloodstream – and white blood cells accumulate in the arterial wall.

White blood cells are white knights in the bloodstream, essential cogs in the immune system that seek out and destroy foreign bacteria and viruses. But they can be turned against the body as well.

Fan's group is learning what causes good-guy macrophages, an important type of white blood cell that is the first line of defense against infection, to turn into bad-guy plaque components, engorged with excessive lipids that cause inflammation in the arterial wall. Their results are promising so far: They've identified a way that they might reduce or prevent the inflammation that is a crucial part of plaque buildup.

"Blocking the signaling initiated by a cell surface protein called TLR4 may be an effective approach for halting the disease," he says. "Now, we are trying to develop a small molecule derived from a Chinese herb as such a blocker."

Inflammation and macrophages are threads that connect atherosclerosis to cancer as well. In addition to warding off external threats like bacteria and viruses, macrophages are on the front lines in the battle to keep cancer in check, targeting and destroying cells with damaged DNA.

But with cancer, macrophages can be turncoats as well. Malignant cells produce slightly different macrophages, called tumor-associated macrophages, which, rather than destroying malignant cells, instead help them grow and spread.

Working to identify compounds in Chinese herbs that reduce inflammation and help prevent atherosclerosis, Fan's team identified a promising candidate for reining in the rogue tumor-associated macrophages, reclaiming them as good guys once again.

Fan recognizes the importance of taking multiple approaches to understanding a problem – determining the biochemical mechanism of action, preparing derivatives through synthesis, verifying results in animal models. He sees a multipronged approach as a key to success.

It's a particularly time-consuming process, but each insight is another step forward in understanding all the connections and making it possible to transform sickness into good health. "The road will be long," he says. "It is hope that makes us enjoy every step, big or small."


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