Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Intercepting inflammation

02.08.2010
Genetic data help scientists close in on the immunological malfunctions underlying a mysterious pediatric disorder

Scientists and doctors continue to find themselves baffled by Kawasaki disease (KD), an inflammatory disorder that represents the leading cause of pediatric heart problems in the developed world. “The cause of KD has remained unknown for more than 40 years since the first description of the disease by Dr. Kawasaki, and so there is no evidence-based therapeutic strategy,” says Yoshihiro Onouchi of the RIKEN Center for Genomic Medicine in Yokohama.

Onouchi has partnered with other scientists in Japan and the United States to identify chromosomal regions containing genes potentially associated with this condition, uncovering strong evidence that KD arises in part from improper regulation of the immune system. Based on this hypothesis, he and his colleagues recently examined loci within chromosomal region 4q35, which contains a diverse array of genes relevant to this process1.

The researchers were especially interested in the gene encoding caspase-3 (CASP3), an enzyme that participates in the initiation of programmed cell death and thereby helps to mitigate the extent of T cell-mediated immune responses. By comparing data from a cohort of Japanese individuals affected with KD relative to their unaffected counterparts, they were able to identify more than two dozen sequence variations near CASP3 that appear to preferentially associate with disease onset.

Functional analysis of the gene revealed the presence of an ‘enhancer’, a stretch of DNA where regulatory proteins can bind to help ratchet up expression levels, surrounding one of the variants identified in this initial screen. The researchers determined that the genomic sequence alteration linked with KD appears to impair enhancer binding by the transcriptional regulator nuclear factor of activated T cells (NFAT), and this reduced NFAT binding in turn leads to significantly reduced CASP3 expression. Importantly, this variant is also significantly associated with disease susceptibility in European populations.

Onouchi and colleagues have previously identified another KD-associated variation (or SNP) in the gene encoding inositol 1,4,5-trisphosphate 3 kinase-C (ITPKC), an enzyme that downregulates a T cell signaling cascade in which calcium ion (Ca2+) flux is coupled with NFAT activation2. In combination, these findings suggest that NFAT may offer a promising drug target. “The calcineurin enzyme plays a key role in the Ca2+/NFAT pathway, and we are now interested in the potential of calcineurin inhibitors like cyclosporin A as a therapeutic option,” says Onouchi. “Our team is now collaborating with several medical institutes in Japan in an attempt to evaluate the effectiveness of cyclosporin A on refractory KD cases.”

The corresponding author for this highlight is based at the Laboratory for Cardiovascular Disease, RIKEN Center for Genomic Medicine

Journal information

1. Onouchi, Y., Ozaki, K., Burns, J.C., Shimizu, C., Hamada, H., Honda, T., Terai, M., Honda, A., Takeuchi, T., Shibuta, S. et al. Common variants in CASP3 confer susceptibility to Kawasaki disease. Human Molecular Genetics published online 10 May 2010 (doi: 10.1093/hmg/ddq176)

2. Onouchi, Y., Gunji, T., Burns, J.C., Shimizu, C., Newburger, J.W., Yashiro, M., Nakamura, Y., Yanagawa, H., Wakui, K., Fukushima, Y. et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nature Genetics 40, 35–42 (2008)

gro-pr | Research asia research news
Further information:
http://www.rikenresearch.riken.jp/eng/research/6344
http://www.researchsea.com

Further reports about: Burns CASP3 CASP3 expression Genetics Honda Kawasaki disease NFAT chromosomal region 4q35 genomic

More articles from Life Sciences:

nachricht Microscope measures muscle weakness
16.11.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

nachricht Good preparation is half the digestion
16.11.2018 | Max-Planck-Institut für Stoffwechselforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: UNH scientists help provide first-ever views of elusive energy explosion

Researchers at the University of New Hampshire have captured a difficult-to-view singular event involving "magnetic reconnection"--the process by which sparse particles and energy around Earth collide producing a quick but mighty explosion--in the Earth's magnetotail, the magnetic environment that trails behind the planet.

Magnetic reconnection has remained a bit of a mystery to scientists. They know it exists and have documented the effects that the energy explosions can...

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Purdue cancer identity technology makes it easier to find a tumor's 'address'

16.11.2018 | Health and Medicine

Good preparation is half the digestion

16.11.2018 | Life Sciences

Microscope measures muscle weakness

16.11.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>