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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." |
