Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

OHSU-led research examines role of copper, iron in diseases

14.01.2004


Interdisciplinary project targets disruptions of metal ion balance in human cells



For years, scientists have worked to pinpoint what causes the short-circuit of copper metabolism in human cells that leads to two deadly neurodegenerative disorders known as Wilson’s disease and Menkes disease.

Now, a research team led by scientists at Oregon Health & Science University is working full time at the molecular level of medicine to find out.


These "metallobiochemists" are part of an interdisciplinary research program that has become one of the first in the nation to focus on understanding metal homeostasis in human cells and its disruption not just in Wilson’s and Menkes diseases, but also diseases such as hemochromatosis, Lou Gehrig’s disease and even mad cow disease, all of which may be linked to errors in metal metabolism.

The research explores molecular mechanisms regulating primarily copper and iron concentrations in normal and diseased cells. The metals are essential to a wide range of biological processes, and aberrations in their metabolism lead to life-threatening and disabling disorders.

Svetlana Lutsenko, Ph.D., associate professor of biochemistry and molecular biology in the OHSU School of Medicine, is leading the multifaceted project titled "Metal Ion Regulation in Human Cells." The effort unites several research laboratories studying the distribution of metals at the molecular, cellular and tissue levels, including teams from OHSU’s schools of medicine, science and engineering, and dentistry, the University of Illinois at Chicago and the California Institute of Technology at Pasadena.

"It’s very important to understand the regulation of metals in cells," Lutsenko said. "It’s a fairly new area of research we really wanted to develop. We’re trying to dissect normal metal metabolism and to understand the effect of metals on disease progression."

Vital to the project’s success is the "metal ion core," a collection of precision lab equipment that includes a mass spectrometer to study metal-induced modifications of proteins; an atomic absorption spectrometer to measure metal concentrations in cell and tissue samples; and a confocal microscope to look at protein "trafficking" within the cell and at distribution of genes involved in metal metabolism in various tissues.

The core "brings us to a new level of accuracy, sophistication, and sensitivity of measurements," Lutsenko said.

Copper, which the human body requires for embryo development, connective tissue formation, temperature control and nerve cell function, is a major focus of the project. The research team is tracking copper movement at three levels: uptake into the cell, which is mediated by a newly discovered protein called hCtrl; delivery to specific copper-dependent molecules within the cell by "metallochaperone" proteins known as Atox1 and hCCS; and removal from the cell by proteins called copper-transporting ATPases.

Of particular interest to the researchers is the chaperone protein Atox1. Researchers hope to learn how Atox1 and the copper-transporting ATPase find each other in a cell, how copper is transferred from Atox1 to disease proteins, which are mutated forms of ATPases, and determine the specific molecular consequences of the copper transfer.

Ninian Blackburn, Ph.D., professor of environmental and biomolecular systems at OHSU’s OGI School of Science & Engineering and a metal ion project investigator, is studying the interaction between the chaperones and target proteins, a system that, under normal conditions, ensures the concentration of free copper is kept at a negligible level.

"There are literally tens of thousands of proteins in a cell," Blackburn said. "How does the cell know where to place the metal in this huge sea of proteins? That’s what the chaperones do. They’re like taxis that collect the metal from the uptake protein at the cell membrane and take it to right target protein. What we’re trying to do is understand how they know where to go, how they actually carry out this feat."

Researchers also will study the structure and function of the copper-transporting ATPases, which are central to the copper metabolism and, when mutated, are associated with Menkes and Wilson’s diseases.

Menkes disease occurs when dietary copper is trapped in intestinal cells and is abnormally low in tissues. According to the National Institute of Neurological Disorders and Stroke, Menkes infants, mostly males, are born prematurely and suffer from stunted development, as well as seizures, failure to thrive, low body temperature, and kinky, colorless and fragile hair. There is no cure for the disease and it is usually fatal by age 10.

Wilson’s disease is caused when excessive copper accumulates in the body, leading to liver disease in about 40 percent of patients as well as neurological problems, including tremors, rigidity, drooling, difficulty with speech, abrupt personality change, and unusual behavior associated with neurosis and psychosis. If untreated, it is generally fatal by age 30.

Iron metabolism and its link to hemochromatosis is being studied as well by OHSU investigators. An inherited disease, hemochromatosis occurs when the body absorbs and stores too much iron, allowing it to build up in the liver, heart and pancreas and triggering their failure. Caroline Enns, Ph.D., professor of cell and developmental biology in the OHSU School of Medicine, is tracking the defective gene that causes the disease.

"There is a very tight link between copper and iron metabolism," Lutsenko said. "Studying the systems in parallel is mutually beneficial. The experimental approaches will be very similar and we expect to discover interesting connections."

The metal ion project began earlier this year following grants from the Oregon Opportunity medical research funding effort and the National Institute of General Medical Sciences. It is the product of a National Institutes of Health program called "Metals in Medicine" that promotes studies on the ways organisms control metal ion transition in cells, and the roles that metals play on cellular regulation and cell-to-cell signaling.

The "Metals in Medicine" program is among the priorities of the United States Public Health Service’s "Healthy People 2010" initiative, a set of health objectives for the nation to achieve over the first decade of the new century.

"There’s definitely an increased awareness of the importance of metal ions in the general medical research community," Blackburn said. "We have had a lot of interest from colleagues who realize the importance of these metals."

Menkes and Wilson’s diseases are just two examples of diseases that are linked to aberrant copper metabolism, he said.

"Anemias are iron deficiencies. The ability of cancers to generate vascular systems has been linked to the roles of various metals complexes," Blackburn explained. "So there are growing numbers of diseases that are known or suspected of being associated with deficiencies in these metal transport processes."

He added that the work of the metal ion research group involves "really getting down to the nitty-gritty within the cell."

"As scientists these days, in order to really understand disease, we have to understand the cell functions at the molecular level," he said. Proteins "are like these little molecular machines that handle all this complex chemistry that goes on in the cell

Jonathan Modie | EurekAlert!
Further information:
http://www.ohsu.edu/
http://www.ohsu.edu/news/

More articles from Interdisciplinary Research:

nachricht Investigating cell membranes: researchers develop a substance mimicking a vital membrane component
25.05.2018 | Westfälische Wilhelms-Universität Münster

nachricht New approach: Researchers succeed in directly labelling and detecting an important RNA modification
30.04.2018 | Westfälische Wilhelms-Universität Münster

All articles from Interdisciplinary Research >>>

The most recent press releases about innovation >>>

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

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Global study of world's beaches shows threat to protected areas

19.07.2018 | Earth Sciences

New creepy, crawly search and rescue robot developed at Ben-Gurion U

19.07.2018 | Power and Electrical Engineering

Metal too 'gummy' to cut? Draw on it with a Sharpie or glue stick, science says

19.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>