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Joseph Beckman
Director, Environmental Health Sciences Center
Professor, Biochemistry and Biophysics
Principal Investigator, Linus Pauling Institute
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RESEARCH:
The first major project in the laboratory is aimed at understanding how oxidative stress, superoxide dismutase and zinc are involved in Lou Gehrig's disease, also known as amyotrophic lateral sclerosis (ALS). ALS is a dreadful disease killing about 5,000 Americans each year. The disease is caused by the unexplained death of motor neurons in the spinal cord. These neurons control the movement of all voluntary muscles. As more and more motor neurons die, the victim's muscles progressively atrophy and they become paralyzed. Mutations to an antioxidant enzyme called superoxide dismutase are the only known cause of ALS. Our research indicates that the loss of zinc from superoxide dismutase is what causes motor neurons to die in ALS. This gives us a chemical target to develop new treatments in the laboratory. One compound we have identified by cell culture tests is also the most protective compound yet identified in animal models of ALS. We are using powerful new tools involving rapid molecular evolution to derive novel proteins that will inactivate zinc-deficient superoxide dismutase. We have developed new methods that robots can use to rapidly screen hundreds of thousands of existing drugs and other compounds, including dietary constituents, for therapeutic benefits. We are characterizing how zinc is handled in motor neurons and why superoxide dismutase can become zinc deficient in ALS. Our goal is to understand how superoxide dismutase causes ALS and to find new ways to stop the disease.
The second major project in the laboratory focuses on the roles of nitric oxide, peroxynitrite and nitrotyrosine in human disease. The major function of superoxide dismutase is to scavenge the oxygen radical superoxide. We discovered that a major target for superoxide is nitric oxide. Until fifteen years ago, nitric oxide was only considered as a toxic air pollutant, damaging the lung and promoting cancer by damaging DNA. However, nitric oxide is also produced by cells lining the arterial walls to relax the underlying smooth muscle and increase blood flow. For example, nitric oxide is the active metabolite produced from nitroglycerin that stops angina in heart disease patients. Viagra works by prolonging the effects of nitric oxide in blood vessels in the penis to maintain erections. Nitric oxide also has a "dark side" and, following reaction with superoxide to produce the powerful oxidant peroxynitrite, can promote oxidative damage to blood vessels, skin, heart, lung, kidney and brain. We are characterizing the role of peroxynitrite in injuring cells and how cells respond to this damage. One sign of damage left by peroxynitrite is nitration of amino acids in proteins. We have identified a variety of such proteins modified in tissues. We hypothesize that nitration is particularly important as a defense against viral infections, damaging proteins and RNA necessary for viral replication, but at the same time can be damaging to host tissues and cells, thereby contributing to acute injury and chronic disease.