SCIENCE TIP SHEET June 1998
Contacts:
Karen Young Kreeger (215) 662-2560, [email protected] or
Franklin Hoke, [email protected]
Philadelphia, Pa. -- Below are three story ideas based on ongoing research at the University of Pennsylvania Medical Center.
Seeing Blue-Yellow Color Perception for the First Time: Color vision has been studied for centuries, but the molecular and cellular intricacies of its neural circuitry have remained an enigma, until now. As reported in a May issue of the Journal of Neuroscience, Penn researchers, led by Peter Sterling, PhD, have -- for the first time -- determined the wiring, neurochemical pathways, and three-dimensional layout of cells in the retina that are involved in blue-yellow color vision that is evident in all mammals. Knowledge of this retinal structure and biochemistry will lay the foundation for designing artificial retinas and better understanding rare eye diseases. Using the intact retina of a macaque, the scientists created a three-dimensional map of the location of the blue-yellow cells by taking electron micrographs of 320 cross-sections of the retina. "We photographed the mosaic of retinal cells piece by piece, analyzed over 2,000 images, and then used a computer program to ! build up a library of the complete structure," explains Sterling, a professor of neuroscience. "By composing this exacting model, we can now isolate and identify the interacting circuitry between layers of the retina." The findings of Sterling's group also provide clues to the neural processes at work in red-green vision -- the additional, complementary color-vision system that is found in all Old World primates, including humans. Indeed, anthropologists surmise that the red-green system evolved in these primates to allow them to distinguish red, ripe fruits from green tree foliage and to discriminate gender-specific markings during mating season.
Understanding the Mystery of Anesthesia: What is the precise physical and mental state produced by anesthetic drugs? Despite a century and a half of reliance on these drugs to advance life-saving surgical techniques, physicians and scientists still don't know the answer to that question. "All we know for sure when we give patients anesthetic drugs is that they don't respond to pain and they don't remember the experience," says Roderic G. Eckenhoff, MD, an associate professor of anesthesiology and physiology. "We don't know how the drugs work or even where in the central nervous system they act to produce their effects on consciousness." Eckenhoff is leading a multidisciplinary research effort to identify the molecular mechanism -- or mechanisms -- of action for the small, two- or three-carbon molecules that produce anesthesia. For years, researchers in this area have searched in vain for a single molecular interaction, whether with a receptor protein or cell-membrane lipid, t! o explain the drugs' effects. Eckenhoff suggests that, while it would be simpler for investigators if this were the case, it is more likely that the drugs act at multiple sites in a complex, coordinated manner. "We're beginning to understand how these small molecules interact with and bind to proteins, and how that binding changes protein structure and dynamics. It would be premature for us to link these changes with anesthesia, but our early evidence is pointing toward a generalized mechanism of action for inhaled anesthetics." While the ultimate goal of the experimental studies is to improve safety and extend the control physicians have over the anesthetic state, Eckenhoff also hopes the project will build a base of new knowledge that will lead indirectly to other advances. "There will be spinoffs from this work in other fields, some as yet unanticipated, others at least speculatively in view. For example, there's a small literature building now on the use of these kinds of ! drugs for tissue and organ preservation, and thus our research could contribute to transplantation medicine." Also, anesthesia is not like ordinary sleep or other types of unconsciousness, Eckenhoff notes, raising questions about the nature of consciousness itself that might be illuminated by the studies. "Once we better understand how unconsciousness works, chances are we'll have new insight into how consciousness works."
Platelet Receptor Biology is Key to Fighting Heart Disease: 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 st! ate 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.
News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page (http://www.med.upenn.edu), to the electronic news service SciNews-MedNews.
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