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 Algae: The final frontier
22.06.2017 | Carnegie Institution for Science

nachricht Flipping the switch to stop tumor development
22.06.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

Im Focus: Optoelectronic Inline Measurement – Accurate to the Nanometer

Germany counts high-precision manufacturing processes among its advantages as a location. It’s not just the aerospace and automotive industries that require almost waste-free, high-precision manufacturing to provide an efficient way of testing the shape and orientation tolerances of products. Since current inline measurement technology not yet provides the required accuracy, the Fraunhofer Institute for Laser Technology ILT is collaborating with four renowned industry partners in the INSPIRE project to develop inline sensors with a new accuracy class. Funded by the German Federal Ministry of Education and Research (BMBF), the project is scheduled to run until the end of 2019.

New Manufacturing Technologies for New Products

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Innovative LED High Power Light Source for UV

22.06.2017 | Physics and Astronomy

Mathematical confirmation: Rewiring financial networks reduces systemic risk

22.06.2017 | Business and Finance

Spin liquids − back to the roots

22.06.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>