Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UT Southwestern researchers show absence of key oxygen-sensing molecule leads to developmental defects

25.11.2003


UT Southwestern Medical Center at Dallas researchers have shown that the absence of a key oxygen-sensing molecule can lead to multiple developmental defects - from an enlarged heart to eye problems.



The researchers generated the first mouse model that lacks entirely a member of an important family of proteins involved in sensing hypoxia, a state of reduced oxygen in the body’s cells that is associated with conditions such as heart attacks, stroke and lung disease.

This new model allowed the scientists to take a closer look into the exact physiologic function of these proteins, which was unknown until now, and the model provided clues as to what human diseases may be caused by alterations in these proteins. The researchers reported in the online version of Nature Genetics that the absence of this crucial oxygen-sensing molecule leads to developmental defects due to the inability of the mice to respond to high, damaging levels of oxygen-based molecules called reactive oxygen species.


Their knockout mice lacked the gene Epas1, which encodes HIF-2a (hypoxia inducible factor 2a ), a molecule activated in response to hypoxia. In the mice that lacked HIF-2a, the researchers reported abnormalities including cardiac hypertrophy or enlarged heart, fatty liver, eye defects, serum biochemical abnormalities, and increased oxidative stress - conditions seen in human patients with mitochondrial defects.

"The surprise was that mice lacking the nuclear DNA-encoded Epas1/HIF-2a had changes in multiple organs that was suggestive of a mitochondrial disease state," said Dr. Joseph Garcia, assistant professor of internal medicine and senior author of the study. "Both mitochondrial and nuclear DNA mutations can adversely affect these crucial intracellular organelles and lead to widespread abnormalities in humans as well as animal models."

The body has a normal response to hypoxia, which includes turning on specific genes that have protective roles to alleviate the detrimental effects of reduced oxygen in the cells. It likewise has an adaptive response to oxidative stress that involves increasing the expression of genes whose function is to eliminate oxygen radicals and their potentially harmful derivatives.

"This study provides evidence that Epas1/HIF-2a is an important regulator of gene expression for a particular group of genes involved in oxidative stress response," Dr. Garcia said. "In the absence of Epas1/HIF-2a, mice are not able to turn on the expression of these antioxidant genes, and the overall balance of the cell favors a state of oxidant excess, which led us to hypothesize that the mitochondria in the Epas1/HIF-2a knockout mice were impaired.

"We attributed the cause of impairment to increased oxidative stress and decreased elimination of reactive oxygen species."

To test their hypothesis, the researchers treated the mice with a chemical compound that mimics the activity of proteins encoded by genes that Epas1/HIF2a would normally activate. This chemical compound, which has antioxidant properties, substantially prevented or reversed the organ and metabolic abnormalities in the mice. In addition, treatment of pregnant females with the same molecule led to increased viability in their newborns, suggesting that "therapy that reduces oxidative stress, increases (newborn) survival to birth," the researchers reported.

"This research also has implications for a role of Epas1/HIF-2a and possibly other HIF factors in human mitochondrial disorders," Dr. Garcia said. "Their role in other human conditions associated with increased oxidative stress such as aging, cardiovascular disease and diabetes will require future studies."

Other researchers who contributed to the study included Dr. Michael Bennett, professor of pathology and pediatrics; Dr. Kan Ding, postdoctoral researcher in internal medicine; Yavuz Oktay, student research assistant in the Integrative Biology Graduate Program; Dr. James Richardson, professor of pathology; Dr. Marzia Scortegagna, postdoctoral researcher in internal medicine; John Shelton, a research scientist in internal medicine; Arti Gaur, a former research assistant in internal medicine; and researchers at the University of Washington School of Medicine.

The study was funded by the National Institutes of Health, the American Heart Association and the Donald W. Reynolds Foundation.

Amy Shields | UT Southwestern
Further information:
http://www8.utsouthwestern.edu/utsw/cda/dept37389/files/129258.html

More articles from Life Sciences:

nachricht New switch decides between genome repair and death of cells
27.09.2016 | University of Cologne - Universität zu Köln

nachricht A blue stoplight to prevent runaway photosynthesis
27.09.2016 | National Institute for Basic Biology

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First quantum photonic circuit with electrically driven light source

Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.

Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...

Im Focus: OLED microdisplays in data glasses for improved human-machine interaction

The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.

“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...

Im Focus: Artificial Intelligence Helps in the Discovery of New Materials

With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.

Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...

Im Focus: Complex hardmetal tools out of the 3D printer

For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.

Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...

Im Focus: Launch of New Industry Working Group for Process Control in Laser Material Processing

At AKL’16, the International Laser Technology Congress held in May this year, interest in the topic of process control was greater than expected. Appropriately, the event was also used to launch the Industry Working Group for Process Control in Laser Material Processing. The group provides a forum for representatives from industry and research to initiate pre-competitive projects and discuss issues such as standards, potential cost savings and feasibility.

In the age of industry 4.0, laser technology is firmly established within manufacturing. A wide variety of laser techniques – from USP ablation and additive...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Laser use for neurosurgery and biofabrication - LaserForum 2016 focuses on medical technology

27.09.2016 | Event News

Experts from industry and academia discuss the future mobile telecommunications standard 5G

23.09.2016 | Event News

ICPE in Graz for the seventh time

20.09.2016 | Event News

 
Latest News

New switch decides between genome repair and death of cells

27.09.2016 | Life Sciences

Nanotechnology for energy materials: Electrodes like leaf veins

27.09.2016 | Physics and Astronomy

‘Missing link’ found in the development of bioelectronic medicines

27.09.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>