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Fighting heart disease one molecule at a time

Examining a protein’s role in atherosclerosis

Understanding how and why white blood cells attach to blood vessel walls may be critical in treating atherosclerosis, or hardening of the arteries.

Xiaohui “Frank” Zhang, assistant professor in the bioengineering program and the department of mechanical engineering and mechanics, is at the forefront of that effort, thanks to an American Heart Association-funded project that also includes medical doctors from Texas and New York.

Zhang believes the study offers hope in the fight against heart disease – the nation’s number one killer.

“To fight off invading pathogens, your white blood cells — also called leukocytes — leave the bloodstream and migrate into infected tissues,” says Zhang. “To do this, they must attach to and permeate blood vessel walls, aided by adhesion molecules on their surface that also bind to the wall.

“The regulation of this adhesive process is tricky. Too little regulation can lead to overactive white blood cell adhesion, resulting in severe inflammatory or auto-immune diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease.”

Zhang’s team is studying the protein molecule integrin, which mediates the leukocyte-blood vessel interactions. A key integrin-related process occurs when cholesterol is also present in the bloodstream. Left unregulated, integrin helps cholesterol harden and block arteries. But if integrin activity is overly suppressed, the leukocytes’ ability to penetrate blood vessel walls and engulf infections can be compromised.

Thus, researchers are seeking to determine integrin’s optimal level of mediation.

Using optical tweezers at the molecular level and atomic force microscopy at the cellular level, Zhang’s team is measuring integrin’s strength and stability when it combines with other proteins in the body. This will allow the group to gauge the forces required to pull the proteins apart. Once these mechanical dynamics are better understood, says Zhang, advances in the regulation of integrin’s mediating role will follow.

“From an engineering perspective,” he says, “developing the ability to precisely control integrin regulation is complex and fascinating. There is also profound potential for this work to positively impact thousands of lives one day.”

Zhang’s team includes postdoctoral fellow Yizhen Wang, research associate Yan Guo and physics professor Daniel Ou-Yang from Lehigh; Michael Goligorsky of New York Medical College; and Qing Ma and Jeffrey Molldrem at the University of Texas’ M.D. Anderson Cancer Center.