July 3, 1998 Several weeks ago cardiologists representing 72 organizations from all over the world announced that a new drug called tirofiban -- also known as aggrastat -- could reduce the risk of death in unstable angina patients by 47%. The drug attaches to and blocks biochemical doorways on platelet cells called IIb/IIIa receptors. When bound to these receptors, the drug keeps fibrinogen -- a protein found in the blood -- from adhering to platelets, thereby preventing the formation of platelet thrombi, which can cause arterial blockage.
The lab of Joel Bennett, MD, a professor of medicine, has been working on the molecular biology of the IIb/IIIa receptor for the last 20 years. His lab's discovery of the receptor, its amino acid sequence, and how it works in conjunction with proteins like fibrinogen laid the groundwork for these recent clinical advances. In the last year, Bennett and colleagues have been trying to find out how IIb/IIIa gets activated in the first place. Platelets -- via the IIb/IIIa receptor -- remain inactive until needed.
"So now we're studying the way in which IIb/IIIa goes from an inactive state to an active one to eventually figure out how to inhibit platelet aggregation," says Bennett. "Clinically, any drug that would come out of this would be used in the same way as tirofiban, but may have the potential to be more potent in its anti-thrombotic characteristics."
But here's the rub: To study how IIb/IIIa gets activated presents a challenge because platelets are one of the only cells in the body that don't have nuclei, thereby useless for studies in which genetic manipulation of a protein is necessary. In a paper in the June 12 issue of the Journal of Biological Chemistry, Bennett's team describes a new technique in which they have successfully changed and experimented with IIb/IIIa receptors expressed in b-lymphocytes, circumventing the platelet problem. This is the first step in making the necessary discoveries for the next generation of platelet-based, anti-clotting drugs.
The University of Pennsylvania Medical Center's sponsored research and training ranks third in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation -- $175 million in federal fiscal year 1997. In addition, for the third consecutive year, the institution posted the highest annual growth in these areas -- 17.6 percent -- of the top ten U.S. academic medical centers.
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