Featured Research

from universities, journals, and other organizations

Bioengineers identify the cellular mechanisms of traumatic brain injury; New hope for treatment of TBI in veterans wounded by explosions

Date:
July 25, 2011
Source:
Harvard University
Summary:
Bioengineers have identified, for the very first time, the mechanism for diffuse axonal injury and explained why cerebral vasospasm is more common in blast-induced brain injuries than in brain injuries typically suffered by civilians.

Bioengineers at Harvard have identified the mechanism for diffuse axonal injury and explained why cerebral vasospasm is common after an IED explosion.
Credit: Photo courtesy of the U.S. Department of Defense

Bioengineers at Harvard have identified, for the very first time, the mechanism for diffuse axonal injury and explained why cerebral vasospasm is more common in blast-induced brain injuries than in brain injuries typically suffered by civilians.

Related Articles


The research addresses two major aspects of traumatic brain injury (TBI), with significant implications for the medical treatment of soldiers wounded by explosions.

Two papers, published in the journals Proceedings of the National Academy of Sciences (PNAS) and PLoS ONE, provide the most comprehensive explanation to date of how mechanical forces can be translated into subtly disastrous physiological changes within the brain's neurons and vasculature.

"These results have been a long time coming," says principal investigator Kevin Kit Parker, a Professor of Bioengineering at Harvard's School of Engineering and Applied Sciences (SEAS) and a major in the U.S. Army. "So many young men and women are returning from military service with brain injuries, and we just don't know how to help them."

When the brain encounters a jarring force, such as an exploding roadside bomb, the delicate tissue slams against the skull. The result, if the patient survives, can be a temporary concussion, a more dangerous hemorrhage, or long-term TBI, which can even lead to the early onset of Parkinson's or Alzheimer's diseases.

Inspired by Parker's own military experience, the Disease Biophysics Group (based at SEAS and at the Wyss Institute for Biologically Inspired Engineering at Harvard) has taken up the cause. Using cutting-edge tissue engineering techniques -- essentially creating a living brain on a chip -- biologists, physicists, engineers, and materials scientists collaborate to study brain injury and potential targets for treatment.

Now, researchers in his group have identified the cellular mechanism that initiates diffuse axonal injury, offering urgently needed direction for research in therapeutic treatments.

Their studies show that integrins, receptor proteins embedded in the cell membrane, provide the crucial link between external forces and internal physiological changes.

Integrins connect the structural components within the cell (such as actin and other cytoskeletal proteins) with the extracellular matrix that binds cells together into tissue. Collectively, this network of structural and signaling components is referred to as the focal adhesion complex.

Parker's research has demonstrated that the forces unleashed by an explosion physically disrupt the structure of the focal adhesion complex, setting off a chain reaction of destructive molecular signals within the nerve cells of the brain.

Inside the neuron, integrins normally mediate the activation of the proteins RhoA and Rho kinase (ROCK). When the focal adhesion complex is disturbed, the Rho-ROCK signaling pathway goes haywire: it directs the motor protein actin to retract the cell's arm-like axons, disconnecting the neurons from each other and collapsing the cellular networks that constitute the brain.

"Our research has shown that abrupt mechanical forces, such as those from a blast wave and transduced by integrins, can result in neural injury," says Matthew A. Hemphill, who with Borna Dabiri (S.B. '07) and Sylvain Gabriele, is a lead author of the paper in PLoS One. Dabiri and Hemphill are currently graduate students at SEAS, and Gabriele is a former postdoctoral fellow in Parker's lab.

Adds Dabiri: "Encouragingly, we also found that treating the neural tissue with HA-1077, which is a ROCK inhibitor, within the first 10 minutes of injury, reduced the number of focal swellings. We think that further study of ROCK inhibition could lead to viable treatments within the near future."

A second direction of research in Parker's lab has solved another mystery in TBI, explaining why cerebral vasospasm, a dangerous remodeling of the brain's blood vessels, occurs more commonly in TBI caused by explosions than in other types of brain trauma.

"Until now, other researchers looking at TBI focused on ion channels and membrane poration, and it was generally accepted that cerebralvasospasm was only caused by hemorrhaging. It turns out that it's much morecomplicated than that," says Patrick W. Alford, a former postdoctoral fellow in Parker's lab and lead author of the paper in PNAS. "Integrins and Rho-ROCK signaling appear to be players in both diffuse axonal injury and cerebral vasospasm."

As reported in PNAS, the forces exerted on arteries are different during an explosive blast than during blunt force trauma. Subarachnoid hemorrhage, which can occur in very severe head injuries, is known to cause vasospasm, but Parker's new research shows that the unique force of an explosion can also cause vasospasm by itself.

The blast from an explosion creates a surge in blood pressure, which stretches the walls of the blood vessels in the brain. To study this, Parker's team of bioengineers built artificial arteries, made of living vascular cells, and used a specialized machine to rapidly stretch them, simulating an explosion. While this stretching did not overtly damage the cellular structure, it did cause an immediate hypersensitivity to the protein endothelin-1.

Endothelin-1 is known to stimulate vascular cells to absorb calcium ions, which affect actin -- the same protein involved in the retraction of axons.

In the 24 hours following the simulated blast, the vascular tissues hypercontract and undergo a complete phenotypic switch, disrupting the overall function of the tissue. Both of these behaviors are characteristic of cerebral vasospasm.

Most importantly, as in the neural tissue, the Rho-ROCK signaling pathway plays an important role in the behavior of actin and the cells' contraction. Parker's team found that inhibition of Rho soon after the injury can mitigate the harmful effects of the blast on the brain's vascular system.

"We have established a toe-hold as we try to climb up on top of this problem," says Parker. "In many ways, this work is just the beginning."

Parker's coauthors on the paper in PLoS One are Hemphill, currently at the University of Mons in Belgium; Dabiri, who beganworking in Parker's lab as an undergraduate; Gabriele, who is now at the University of Mons; Lucas Kerscher, a visiting student; Christian Franck, formerly a postdoctoral fellow at SEAS and now at Brown University; Josue A. Goss, a staff engineer at SEAS; and Alford, who is now at the University ofMinnesota.

Parker's coauthors on the paper in PNAS are Alford; Dabiri; Goss; Hemphill; and Mark D. Brigham, a graduate student at SEAS.

The Disease Biophysics Group received financial support from the Defense Advanced Research Projects Agency (DARPA) Preventing Violent Explosive Neurologic Trauma (PREVENT) Program, the Department of Defense, and the Harvard School of Engineering and Applied Sciences (SEAS).

The researchers also gratefully acknowledge the use of facilities at the Harvard Center for Nanoscale Systems, a member of the National Nanotechnology Infrastructure Network (NNIN), which is funded by the National Science Foundation (NSF).


Story Source:

The above story is based on materials provided by Harvard University. Note: Materials may be edited for content and length.


Journal References:

  1. P. W. Alford, B. E. Dabiri, J. A. Goss, M. A. Hemphill, M. D. Brigham, K. K. Parker. Blast-induced phenotypic switching in cerebral vasospasm. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1105860108
  2. Matthew A. Hemphill, Borna E. Dabiri, Sylvain Gabriele, Lucas Kerscher, Christian Franck, Josue A. Goss, Patrick W. Alford, Kevin Kit Parker. A Possible Role for Integrin Signaling in Diffuse Axonal Injury. PLoS ONE, 2011; 6 (7): e22899 DOI: 10.1371/journal.pone.0022899

Cite This Page:

Harvard University. "Bioengineers identify the cellular mechanisms of traumatic brain injury; New hope for treatment of TBI in veterans wounded by explosions." ScienceDaily. ScienceDaily, 25 July 2011. <www.sciencedaily.com/releases/2011/07/110722213427.htm>.
Harvard University. (2011, July 25). Bioengineers identify the cellular mechanisms of traumatic brain injury; New hope for treatment of TBI in veterans wounded by explosions. ScienceDaily. Retrieved October 25, 2014 from www.sciencedaily.com/releases/2011/07/110722213427.htm
Harvard University. "Bioengineers identify the cellular mechanisms of traumatic brain injury; New hope for treatment of TBI in veterans wounded by explosions." ScienceDaily. www.sciencedaily.com/releases/2011/07/110722213427.htm (accessed October 25, 2014).

Share This



More Mind & Brain News

Saturday, October 25, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Academic Scandal Shocks UNC

Academic Scandal Shocks UNC

AP (Oct. 23, 2014) A scandal involving bogus classes and inflated grades at the University of North Carolina was bigger than previously reported, a new investigation found. (Oct. 23) Video provided by AP
Powered by NewsLook.com
Working Mother Getaway: Beaches Turks & Caicos

Working Mother Getaway: Beaches Turks & Caicos

Working Mother (Oct. 22, 2014) Feast your eyes on this gorgeous family-friendly resort. Video provided by Working Mother
Powered by NewsLook.com
What Your Favorite Color Says About You

What Your Favorite Color Says About You

Buzz60 (Oct. 22, 2014) We all have one color we love to wear, and believe it or not, your color preference may reveal some of your character traits. In celebration of National Color Day, Krystin Goodwin (@kyrstingoodwin) highlights what your favorite colors may say about you. Video provided by Buzz60
Powered by NewsLook.com
First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

Newsy (Oct. 21, 2014) A medical team has for the first time given a man the ability to walk again after transplanting cells from his brain onto his severed spinal cord. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins