Featured Research

from universities, journals, and other organizations

Gene offers clues to new treatments for a harmful blood clotting disorder

Date:
May 8, 2013
Source:
Penn State
Summary:
A gene associated with both protection against bacterial infection and excessive blood clotting could offer new insights into treatment strategies for deep-vein thrombosis -- the formation of a harmful clot in a deep vein. The gene produces an enzyme that, if inhibited via a specific drug therapy, could offer hope to patients prone to deep-vein clots, such as those that sometimes form in the legs during lengthy airplane flights or during recuperation after major surgery.

Shown in blue is chromatin -- the condensed form of DNA that the cell remodels to form chromosomes. The PAD4 enzyme decondenses chromatin by loosening up the interaction between DNA and special proteins called histones. The histones modified by PAD4 are shown in fuchsia. This process helps to form both a bacteria-killing NET -- which is comprised of infection-combatting white blood cells called neutrophils -- and the fluffy, scattered ball that comprises a blood clot.
Credit: Wang lab, Penn State University. Originally published in the Journal of Cell Biology (Citation: Wang, Y., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200806072).

A gene associated with both protection against bacterial infection and excessive blood clotting could offer new insights into treatment strategies for deep-vein thrombosis -- the formation of a harmful clot in a deep vein. The gene produces an enzyme that, if inhibited via a specific drug therapy, could offer hope to patients prone to deep-vein clots, such as those that sometimes form in the legs during lengthy airplane flights or during recuperation after major surgery.

The research, which was led by Yanming Wang, a Penn State University associate professor of biochemistry and molecular biology, and Denisa Wagner, senior author with decades of research on thrombosis at the Boston Children's Hospital and the Harvard University Medical School, will be published in in the Online Early Edition of the journal Proceedings of the National Academy of Sciences during the week ending 10 May 2013.

The team's new findings are an extension of previous research by Wang and other scientists. In earlier studies, Wang and his colleagues had revealed that a gene in mice called Pad4 (peptidylarginine deiminase 4) produces an enzyme that plays an important role in protecting the body from infection. The researchers discovered that cells with a functioning PAD4 enzyme are able to build around themselves a protective, bacteria-killing web that is dubbed a NET (neutrophil extracellular trap).

Now, in their new research, team members have studied the PAD4 enzyme's role in clotting. Wang explained that, as a part of its NET-producing duties, PAD4 regulates the formation of chromatin -- the condensed form of DNA that the cell remodels to form chromosomes. "PAD4 decondenses chromatin by loosening up the interaction between DNA and special proteins called histones. The resulting chromatin threads then combine with protein fibers, blood platelets, and other materials to become, not only the bacteria-killing NET, but also the fluffy, scattered ball that comprises a blood clot." Wang added that, in some individuals, blood clots tend to form within deep veins. These clots can then travel to the heart, causing cardiac arrest, or to the lungs, causing breathing problems.

In one of their experiments, team members compared mice with a normally functioning Pad4 gene to mice with a defective gene. They found that, when veins were constricted, genetically normal mice -- those able to produce the PAD4 enzyme -- formed clots as expected. However, genetically mutated mice -- those unable to produce the enzyme -- did not form clots normally. In fact, the scientists noted a two-fold difference in clot formation between genetically normal and genetically abnormal mice at six hours after the procedure. After 48 hours, the difference had reached 10-fold. "We noted some clotting activity in these genetically abnormal mice, but the clots were not as bulky and were not maintained over time," Wang said. "Clearly, the PAD4 enzyme plays a critical role in the formation of a blood clot, as well as in the formation of a bacteria-fighting NET."

In another experiment, the research team transferred infection-combatting white blood cells -- called neutrophils -- from normal mice to genetically mutated mice. First author Kim Martinod, a graduate student in the Immunology Graduate Program at the Harvard University Medical School, found that, in response to vein constriction, these "rescued" mice now could function normally, forming clots as efficiently as mice with a functioning Pad4 gene, demonstrating that the Pad4 gene did produce a functioning PAD4 enzyme in these white blood cells to regulate blood clotting.

"PAD4, which is also called PADI4 in humans, is a necessary enzyme involved in multiple disorders," Wang explained. "On the one hand, it plays an integral part in the body's defense system, as we showed in earlier work: It is necessary in the production of the protective, bacteria-killing NET. On the other hand, our earlier work also showed that this enzyme acts to silence tumor-suppressor genes. Now, in our new research, we are starting to see that its overactivity also may be part of the reason that some individuals suffer from deep-vein clotting." Wang added that patients prone to deep-vein thrombosis might benefit from drugs that target the PAD4 enzyme. "In future research, specific drug therapies could be developed and tested with the goal of targeting this enzyme," Wang said. "If we could find a way to dial back the enzyme's clot-forming effects, we might be able to offer new hope to patients suffering from clotting disorders and deep-vein thrombosis."

In addition to Wang, Wagner, and Martinod, other scientists who contributed to this research include Jing Hu from Penn State; Melanie Demers, Tobias A. Fuchs, Siu Ling Wong, and Alexander Brill from the Harvard University Medical School and Boston Children's Hospital; and Maureen Gallant from Boston Children's Hospital.

The research was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health and the National Cancer Institute.


Story Source:

The above story is based on materials provided by Penn State. The original article was written by Katrina Voss. Note: Materials may be edited for content and length.


Journal Reference:

  1. K. Martinod, M. Demers, T. A. Fuchs, S. L. Wong, A. Brill, M. Gallant, J. Hu, Y. Wang, D. D. Wagner. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1301059110

Cite This Page:

Penn State. "Gene offers clues to new treatments for a harmful blood clotting disorder." ScienceDaily. ScienceDaily, 8 May 2013. <www.sciencedaily.com/releases/2013/05/130508093050.htm>.
Penn State. (2013, May 8). Gene offers clues to new treatments for a harmful blood clotting disorder. ScienceDaily. Retrieved September 2, 2014 from www.sciencedaily.com/releases/2013/05/130508093050.htm
Penn State. "Gene offers clues to new treatments for a harmful blood clotting disorder." ScienceDaily. www.sciencedaily.com/releases/2013/05/130508093050.htm (accessed September 2, 2014).

Share This




More Health & Medicine News

Tuesday, September 2, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Snack Attack: Study Says Action Movies Make You Snack More

Snack Attack: Study Says Action Movies Make You Snack More

Newsy (Sep. 2, 2014) You're more likely to gain weight while watching action flicks than you are watching other types of programming, says a new study published in JAMA. Video provided by Newsy
Powered by NewsLook.com
U.N. Says Ebola Travel Restrictions Will Cause Food Shortage

U.N. Says Ebola Travel Restrictions Will Cause Food Shortage

Newsy (Sep. 2, 2014) The U.N. says the problem is two-fold — quarantine zones and travel restrictions are limiting the movement of both people and food. Video provided by Newsy
Powered by NewsLook.com
Doctors Fear They're Losing Battle Against Ebola

Doctors Fear They're Losing Battle Against Ebola

AP (Sep. 2, 2014) As a third American missionary is confirmed to have contracted Ebola in Liberia, doctors on the ground in West Africa fear they're losing the battle against the outbreak. (Sept. 2) Video provided by AP
Powered by NewsLook.com
Tech Giants Bet on 3D Headsets for Gaming, Healthcare

Tech Giants Bet on 3D Headsets for Gaming, Healthcare

AFP (Sep. 2, 2014) When Facebook acquired the virtual reality hardware developer Oculus VR in March for $2 billion, CEO Mark Zuckerberg hailed the firm's technology as "a new communication platform." Duration: 02:24 Video provided by AFP
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:
from the past week

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