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Cell death following blood 'reflow' injury tracked to natural toxin
November 30, 2006Researchers at Johns Hopkins have discovered what they believe is the "smoking gun" responsible for most tissue and organ damage after a period of blood oxygen loss followed by a sudden restoration of blood oxygen flow.
Working with mice, the Hopkins team found that the sudden oxygen bath triggered by restored blood flow causes cells to make a chemical so toxic it kills the cells. The work was published in two papers in the Proceedings of the National Academy of Sciences last week.
Although not sure why it happens, the Hopkins scientists believe the toxic chemical, PAR-polymer, acts like a molecular sledgehammer, or a death switch. "We've found evidence of it in cells following all types of injury," says Ted Dawson, M.D., Ph.D., the Leonard and Madlyn Abramson Professor of Neurodegenerative Diseases, professor of neurology and co-director of Hopkins' Neuroregeneration and Repair Program in the Institute of Cell Engineering (ICE).
The research team has named the cell death process caused by PAR-polymer "parthanatos," after Thanatos, the personification of death from Greek mythology.
To establish that PAR-polymer is indeed the culprit in the kind of reperfusion injuries long linked to heart attacks, strokes and a variety of blood vessel injuries, the researchers pumped mouse nerve cells full of PAR-polymer. The cells died, but to be sure PAR-polymer (and not something else) killed them, they examined the brains of mice engineered to lack an enzyme that chews up and gets rid of PAR. These mouse brains contained twice as much PAR-polymer as those of normal mice.
After the researchers induced a blood clot injury like a stroke, the same mice showed a 62 percent increase in the area of brain damage compared to normal littermates. Mice that contain more of the PAR-chewing enzyme suffered less brain damage than their normal littermates.
To figure out what triggers the death switch, the researchers tracked PAR-polymer's journey after cells made it. After 15 minutes, PAR-polymer hadn't gone anywhere. But after 30 to 60 minutes, the researchers discovered that much of it traveled right to areas where the switch normally resides.
The fate of the cell is irreversible once PAR-polymer sets off the trigger, says Valina Dawson, Ph.D., professor of neurology, co-director of the Neuroregeneration and Repair Program and author of the papers. "If we could figure out how to block PAR-polymer, we could design drugs that protect the switch and prevent cells from dying after heart attacks, stroke or other injuries," she says.
Johns Hopkins Medical Institutions
The research team has named the cell death process caused by PAR-polymer "parthanatos," after Thanatos, the personification of death from Greek mythology.
To establish that PAR-polymer is indeed the culprit in the kind of reperfusion injuries long linked to heart attacks, strokes and a variety of blood vessel injuries, the researchers pumped mouse nerve cells full of PAR-polymer. The cells died, but to be sure PAR-polymer (and not something else) killed them, they examined the brains of mice engineered to lack an enzyme that chews up and gets rid of PAR. These mouse brains contained twice as much PAR-polymer as those of normal mice.
After the researchers induced a blood clot injury like a stroke, the same mice showed a 62 percent increase in the area of brain damage compared to normal littermates. Mice that contain more of the PAR-chewing enzyme suffered less brain damage than their normal littermates.
To figure out what triggers the death switch, the researchers tracked PAR-polymer's journey after cells made it. After 15 minutes, PAR-polymer hadn't gone anywhere. But after 30 to 60 minutes, the researchers discovered that much of it traveled right to areas where the switch normally resides.
The fate of the cell is irreversible once PAR-polymer sets off the trigger, says Valina Dawson, Ph.D., professor of neurology, co-director of the Neuroregeneration and Repair Program and author of the papers. "If we could figure out how to block PAR-polymer, we could design drugs that protect the switch and prevent cells from dying after heart attacks, stroke or other injuries," she says.
Johns Hopkins Medical Institutions
Cell Death Current Events and Cell Death News RSSNew understanding about mechanism for cell death after stroke leads to possible therapy
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Researchers find potential treatment for Huntington's disease
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Research reveals lipids' unexpected role in triggering death of brain cells
The lipid that accumulates in brain cells of individuals with an inherited enzyme disorder also drives the cell death that is a hallmark of the disease, according to new research led by St. Jude Children's Research Hospital investigators.
Cornell researchers identify a weak link in cancer cell armor
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Sponges recycle carbon to give life to coral reefs
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Aileron collaborates study in Nature: Stapled peptides inhibit Notch1 transcription factor
This research validates the potential for Stapled Peptides to modulate key intracellular biological targets, such as transcription factors, that have not been addressable with current small molecule or biologic drug modalities.
CSHL team solves structure of NMDA receptor unit that could be drug target for neurological diseases
A team of scientists at Cold Spring Harbor Laboratory (CSHL) reports on Thursday their success in solving the molecular structure of a key portion of a cellular receptor implicated in Alzheimer's, Parkinson's, and other serious illnesses.
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