Hypoxia-induced injury occurs in the case of heart attack, stroke or other neurological or respiratory conditions which diminish the supply of oxygen to vital tissues and organs. Scientists know that most life forms are able somehow to suppress non-essential activity in order to survive oxygen deprivation, but they didn't know why or how this metabolic slowdown occurs.

Because cellular mechanisms in fruit flies are very similar to those in human cells, the research team developed and studied a strain of fly that developed a tolerance to severe hypoxic conditions through adaptive changes over many generations. In looking at more than 13,000 or about 90 percent of the known genes in the genome of the fruit fly, the researchers were able to examine the difference in gene expression profiles between the hypoxia-tolerant and normal Drosophila melanogaster.

"We discovered that the hairy gene binds to and shuts off, or suppresses, activation of many genes," said principal investigator Gabriel G. Haddad. "When hairy is activated, it puts the brakes on various signaling pathways in the cell, enabling the cells to become resistant to the low-oxygen environment." The hairy switch appears to put into motion a sort of "brown out" in the cells, allowing them to conserve power for critical functions. "While there are multiple pathways that contribute to the ability of this strain of flies to tolerate hypoxia, our study demonstrates that hairy-mediated metabolic suppression plays a critical role," said Haddad.

The researchers hope that by better understanding how the Drosophila cells have developed a strategy for survival under the stress of hypoxia, they may be able to help human cells and tissues adapt and survive under low oxygen situations caused by disease.

plosgenetics

"This is a perfect example illustrating why we study genetics in the mouse," said Gan, who is associate professor in the Department of Ophthalmology at the University of Rochester Eye Institute. "We've been able to pinpoint a gene that may play a role in a disease affecting thousands of people, and the work would have been impossible to do directly in people. We did the research in mice, and now we can go back to take a closer look in patients."

Last year, the Rochester team showed that Bhlhb5 plays a role in determining what types of neurons are created in the eye. The eye is the usual focal point for Gan, who is director of the De Stephano Laboratory for Retinal Genomics at the University of Rochester Medical Center. His team studies the genes that play a role in creating the eye, keeping it healthy, and which might play a role in blinding eye diseases such as retinitis pigmentosa, macular degeneration, and glaucoma.

The work includes two corresponding authors: Macklis, who is director of the Center for Nervous System Repair of Massachusetts General Hospital and Harvard Medical School, and Gan, who is also a researcher in the Department of Neurobiology and Anatomy, the Center for Neural Development and Disease, and the Center for Visual Science at Rochester.

The first author is Pushkar S. Joshi, Ph.D., Gan's former graduate student at Rochester, who is now a researcher at Stanford. Other authors include Bradley J. Molyneaux, M.D., Ph.D., formerly Macklis' graduate student at Harvard, who is now a neurology resident there; former Rochester research Liang Feng, Ph.D., now at Northwestern; and Rochester technician Xiaoling Xie.

The work was supported by the National Eye Institute, the National Institute of Neurological Disorders and Stroke, Research to Prevent Blindness, Harvard Stem Cell Institute, the Spastic Paraplegia Foundation, and the ALS Assn.

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