University of Florida researchers reveal secret lives of genes during spinal injury

The body attempts to heal a damaged spinal cord in much the same way it repairs skin after simple cuts and scrapes, an insight that may lead to new treatments for the thousands of people paralyzed each year because of spinal cord injuries, say scientists at the University of Florida Health Science Center.

Writing in the current Journal of Neuroscience, scientists deliver the first-ever glimpse of how thousands of genes swing into action during the weeks and months after a spinal cord injury, suggesting there may be many more chances to treat the injury than commonly thought.

Using a microarray, a powerful tool that screens the activity of more than 8,000 genes simultaneously, researchers checked at six time points after spinal injury in rats and found that 3,638 genes turned on or off in response. The first genes to enter the fray are remarkably similar to those that drive clot formation and the mobilization of immune cells that fix skin wounds.

“Dermal wound healing has been studied for decades,” said Margaret “Jo” Velardo, Ph.D., an assistant professor of neuroscience and member of UF’s McKnight Brain Institute and the UF Genetics Institute. “Now, with the insights furnished by our study, perhaps spinal injury researchers may take advantage of techniques developed by our wound-healing colleagues and apply them. Our experiments showed that the gene families for tissue, vascular and immune system repair mechanisms appear to follow the same pattern as seen in healing skin.”

A quarter of a million Americans currently live with spinal cord injuries, which usually begin with a sudden, traumatic blow to the spine that fractures or dislocates vertebrae, according to the National Institute of Neurological Disorders and Stroke. The number of new injuries each year is relatively small, but usually occur in young people, striking them down in the prime of life and leaving them to survive for many years afterward with a devastating, debilitating injury. The cost of managing the care of spinal cord injury patients approaches a total of $9 billion each year.

Researchers Henry Baker and Corinna Burger of the molecular genetics and microbiology department and the UF Genetics Institute assembled more than 280,000 bits of information that revealed how armies of genes activated or shut down to deal with the spinal injury, not just within a few days of the injury but for as long as three months afterward.

“The patterns told us that something orderly and amazing was happening,” Velardo said. “That motivated us to perform an in-depth analysis so that we could infer the actual biological events occurring at various time intervals after injury.”

On the first day, researchers found protective genes turned on to preserve what functional tissue remained at the injury site. By the third day, the character of the genes changed dramatically, with growth and repair genes turning on simultaneously with a huge number of cell division genes.

“It is as if the body creates thousands of cellular machines to move in and manufacture what is needed to repair the damage,” Velardo said. “At day 10, we could see the genes increase in expression to repair the ground substance and reform the damaged blood vessels of the spinal cord. From 30 to 90 days, at the gene expression level, we can actually observe the maturation of these new blood vessels and the manufacture of a new type of ground substance that occurs as a wound ages and restructures itself.”

The orchestrated, day-to-day process suggests multiple therapeutic opportunities, depending on which genes are being expressed.

“The gene expression changes are related to repair mechanisms,” said Professor Ed Hall, director of the Spinal Cord and Brain Injury Research Center at the University of Kentucky College of Medicine. “In order to improve repair mechanisms, we need to know which processes to promote or antagonize in the spinal cord. We need more study to go after those pharmacological therapies, but this is a seminal work in the field of spinal cord research.”

The UF research also suggests that someone’s genetic background may dictate response to spinal cord injury. Scientists compared two strains of rats, one with a normal immune system and one that was deficient in a type of immune cell called a T cell, which is believed to be important in regulating wound-healing processes. The animals had different recovery patterns after injury, with differences in 80 shared wound-healing genes between the two strains of rats.

“It is likely that small differences in important genes can alter the progression and outcome of the injury,” Velardo said. “Likewise, if we fine-tune our results using further experiments, we may pinpoint some genes that turn on in a successful wound-healing process in the skin that somehow are detrimental and may actually inhibit the repair and regeneration of the spinal cord.”

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