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 The Secret of the Rock Drawings
24.05.2019 | Max-Planck-Institut für Chemie

nachricht Chemical juggling with three particles
24.05.2019 | Rheinische Friedrich-Wilhelms-Universität Bonn

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: New studies increase confidence in NASA's measure of Earth's temperature

A new assessment of NASA's record of global temperatures revealed that the agency's estimate of Earth's long-term temperature rise in recent decades is accurate to within less than a tenth of a degree Fahrenheit, providing confidence that past and future research is correctly capturing rising surface temperatures.

The most complete assessment ever of statistical uncertainty within the GISS Surface Temperature Analysis (GISTEMP) data product shows that the annual values...

Im Focus: The geometry of an electron determined for the first time

Physicists at the University of Basel are able to show for the first time how a single electron looks in an artificial atom. A newly developed method enables them to show the probability of an electron being present in a space. This allows improved control of electron spins, which could serve as the smallest information unit in a future quantum computer. The experiments were published in Physical Review Letters and the related theory in Physical Review B.

The spin of an electron is a promising candidate for use as the smallest information unit (qubit) of a quantum computer. Controlling and switching this spin or...

Im Focus: Self-repairing batteries

UTokyo engineers develop a way to create high-capacity long-life batteries

Engineers at the University of Tokyo continually pioneer new ways to improve battery technology. Professor Atsuo Yamada and his team recently developed a...

Im Focus: Quantum Cloud Computing with Self-Check

With a quantum coprocessor in the cloud, physicists from Innsbruck, Austria, open the door to the simulation of previously unsolvable problems in chemistry, materials research or high-energy physics. The research groups led by Rainer Blatt and Peter Zoller report in the journal Nature how they simulated particle physics phenomena on 20 quantum bits and how the quantum simulator self-verified the result for the first time.

Many scientists are currently working on investigating how quantum advantage can be exploited on hardware already available today. Three years ago, physicists...

Im Focus: Accelerating quantum technologies with materials processing at the atomic scale

'Quantum technologies' utilise the unique phenomena of quantum superposition and entanglement to encode and process information, with potentially profound benefits to a wide range of information technologies from communications to sensing and computing.

However a major challenge in developing these technologies is that the quantum phenomena are very fragile, and only a handful of physical systems have been...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

 
Latest News

On Mars, sands shift to a different drum

24.05.2019 | Physics and Astronomy

Piedmont Atlanta first in Georgia to offer new minimally invasive treatment for emphysema

24.05.2019 | Medical Engineering

Chemical juggling with three particles

24.05.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>