Since they lack nuclei ­- the "brains" of cells ­- platelets are thought of as cellular drones, unable to produce specific proteins in response to signals from other cells.

With an unusual use of human genome project technology, University of Utah scientists have shown that platelets do indeed have the capacity for significant, signal-dependent production of proteins in wound repair and inflammation.

Because platelets also participate in disease, the discovery may present opportunities for development of "smart" drugs to treat heart attack, cancer, stroke, hypertension and many other diseases.

In a paper published in today's edition of the Journal of Cell Biology, Stephan Lindemann, M.D., a cardiology research fellow from Mainz, Germany, and Andrew Weyrich, Ph.D., assistant professor of internal medicine, showed platelets are "armed and dangerous," carrying protein assembly lines that are ready to go at the first hint of signal.

This report is the third in a recent series of papers published by a research team led by Guy Zimmerman, director of the Human Molecular Biology and Genetics program at the university.

Significantly, a protein produced by these assembly lines is a major player in causing inflammation, a normal response to vessel damage.

Usually, cells produce the proteins they need by first transcribing DNA into RNA transcripts and then using the transcript to start an "assembly line" to build the protein.

Platelets lack the beginning of the assembly line ­- nuclei. Instead, the research group found, they have an unusual setup: they carry many RNA transcripts made at an earlier stage in their development, when they do have nuclei.

Unexpectedly, some transcripts for proteins are already attached to the ribosome "assembly line," ready to start production at a moment's notice. This setup, called a polysome, allows platelets to produce a significant amount of protein very quickly.

"Platelets serve as ready response troops for vessel damage," Zimmerman says.

This surprising finding indicates that platelets may have a much bigger role than simply stanching blood flow from damaged vessels.

"Now we know that platelets can, in response to external signals, produce proteins that contribute to repair mechanisms," Zimmerman said.

Specifically, his research team found that platelets produce
interleukin-1-beta (IL-1b), a protein that signals lining cells of damaged vessels to display receptors for white blood cells, key players in inflammation and tissue repair.

Since platelets are first to arrive at the scene when vessel damage occurs, their ability to produce signaling proteins that attract white blood cells as well as to plug leaks is medically significant because it offers new insights into ways to influence vessel repair.

The observations may also point the way to strategies for developing more specific, targeted drugs to treat related diseases.

By using an arrayed cDNA library to identify and locate the IL-1b transcript in the platelets, Lindemann and Weyrich completed in several months a project that could have lasted over ten years. Array technology was developed for the human genome project, and is now used in many biomedical research applications.

To use this technology, Lindemann and Weyrich first removed many mRNA molecules from platelets and analyzed them with a library of 588 cDNAs to identify the transcripts. At least 35 different mRNA transcripts, including the one for IL-1b, were found.

Identifying genes or transcripts via arrays has rapidly become a standard procedure, but the research team employed this technology for an additional, "unusual" task -­ pinpointing the location of the transcripts in the platelets.

The results of these experiments showed that the transcript for IL-1b is present in polysomes, even in non-activated platelets, so that protein production can begin very quickly upon receiving an appropriate signal.

In addition to participating in vessel repair, platelets are implicated in many diseases, from heart attacks to peripheral circulation problems causing strokes, gangrene and other complications. By understanding this novel function of platelets, new possibilities arise for treating these diseases.

For example, doctors treating patients with heart attacks might want to inhibit platelet contributions to inflammation, but some of those patients may also have bleeding disorders that would be aggravated by such treatment.

With this new information regarding platelet function, drugs could be developed to affect platelets' ability to produce new proteins without impairing their ability to plug holes in injured vessels.

Additionally, the results from this study suggest that platelets may release other physiologically significant proteins -- ones that might have roles in tumor growth, hardening of arteries and tissue scarring.

Andrew Weyrich and Stephen Lindemann are affiliated with the university's Human Molecular Biology and Genetics program. Guy Zimmerman, program director, is a professor of internal medicine.

Additional authors include Stephen Prescott, M.D., executive director of the university's Huntsman Cancer Institute and former program director; Tom McIntyre, Ph.D., professor of internal medicine and pathology; Dan Dixon, Ph.D., an instructor in oncological sciences; and Neal Tolley, senior laboratory specialist.

This research was supported by the National Institutes of Health, the Atorvastatin Research Awards and the American Heart Association. - By Kristen Kamerath

[Contact: Kristen Kamerath ]

06-Aug-2001