The currently accepted explanation for why nerve agents are toxic is that they inhibit an enzyme called acetylcholinesterase. When acetylcholinesterase is inhibited, the nervous system no longer works correctly. A large dose of nerve agent can be lethal within minutes. However, people recover from lower doses. After the 1995 Tokyo subway attack by members of the Aum Shinrikiyo cult, 5,000 people were treated in hospitals and 12 people died from exposure to sarin. Of those who survived, some have no symptoms, but others are chronically ill with vision disorders, muscle weakness, and mental disorders. The long-term goal of this research is to find a biochemical explanation for why some people are permanently incapacitated by a single exposure to a nonlethal dose of nerve agent. The immediate goal of this research is to identify new biomarkers of exposure to soman and to develop an improved method for detecting low dose exposure.
Our hypothesis is that acetylcholinesterase is just one of many proteins involved in nerve agent toxicity. This research aims to identify all the proteins in plasma that react with nerve agents. It is likely that the long-term effects of nerve agent exposure are explained by reaction with several proteins rather than just with acetylcholinesterase.
The tasks for this project are to treat human blood with nerve agent, prepare the blood proteins for analysis in the mass spectrometer, and look for peptides modified by binding of nerve agent. The modified peptides will be sequenced and the corresponding proteins identified. The identified proteins will be verified by a second method. These proteins will be tested for their reactivity with low levels of soman.
The anticipated outcome of this research is the identification of several proteins that react with nerve agents. This research will also provide a new method for detecting nerve agent exposure. The benefit to the public is a sensitive method for monitoring possible exposure to nerve agent. In addition, this research will lead to a better understanding of illnesses caused by nerve agent exposure. Once we know which proteins react with nerve agent, we can look for differences in the protein and gene sequences that might explain special sensitivity. Medical treatment strategies can be devised after we know the identities of the proteins that need to be protected.