Mice
live fast lives. They generally are born, grow old and die within two years, their
limited longevity making them ideal for medical research.
“By using mice
in experiments, you can speed up your studies, seeing effects in a month that
would take years to show up in people,” said Stuart Berr, assistant professor
of radiology and biomedical engineering. Mice also serve as good proxies for humans
in medical research since about 99 percent of the approximately 30,000 genes in
humans and mice are essentially identical, inherited from a common ancestor some
75 million years ago. So, genetically engineered mice, in which individual genes
either have been added – as in “transgenic” mice – or subtracted
– as in “knock-out” mice – have become an important tool for
scientists studying how human genes work.
That’s why an estimated
25 million mice now are used in research laboratories around the world. One of
the largest suppliers, The Jackson Laboratory in Bar Harbor, Me., alone sold 1.9
million mice in its most recent fiscal year to research labs, including many at
U.Va., said Joyce Peterson, a Jackson spokeswoman. And demand for the nonprofit
institute’s 3,000 strains of mice is rising by 10 percent a year, she said.
By studying mice that have survived heart attacks – or a myriad of
other human ailments -- researchers can identify new avenues for treatment of
human disease, said Fred Epstein, associate professor of radiology and biomedical
engineering who works with Berr.
According to the American Heart Association,
cardiovascular disease – including high blood pressure, coronary heart disease,
stroke and congestive heart failure -- affects more than 61 million Americans
and is the leading cause of death in the United States, claiming more than 900,000
lives a year.
So, researchers in the U.S. and around the world are seeking
new treatments for cardiovascular disease. But the labor is long and paths are
many, some of which lead nowhere. How can researchers identify the most promising
approaches?
That’s where Berr’s expertise comes in. Berr helps
researchers analyze the results of their experiments by adapting medical imaging
tools to make the measurements they need.
He helps U.Va. researchers with
three different methods of medical imaging that have been adapted for use with
small animals: A magnetic resonance imaging, or MRI, system that has been adapted
to show an image of a tiny mouse heart beating very fast.
A system developed
by Mark Williams, associate professor of radiology, that combines high-resolution,
three- dimensional X-ray scans with images of radioactively labeled compounds
that travel to specific targets (e.g., the lungs, a tumor, etc.).
A bioluminescence
scanner that allows researchers to track cells that have been labeled with light-emitting
proteins, such as firefly luciferase. The images of firefly light are superimposed
onto regular photographs to identify the regions of interest.
Since 1999,
Brent French, a molecular biologist and associate professor of biomedical engineering,
has worked closely with Berr to adapt MRI to mouse research at U.Va. Since then,
the cardiac MRI team has developed several MRI methods for mouse cardiac research
that enable investigators to better understand what happens during a heart attack
and explore ways to minimize the damage after a heart attack.
Another member
of the team, Zequan Yang, assistant professor of research in biomedical engineering,
is using genetically manipulated mice to study the role of inflammation during
heart attacks. “By studying the response to heart attacks in transgenic and
knock-out mice, we can learn what role individual genes play in this process,”
Yang said.
The technical barriers are high. Unlike human hearts, which
beat 60 to 80 times a minute in an average adult, a mouse heart beats about 500
times a minute. And at 7 millimeters long – about the size of Thomas Jefferson’s
head on a nickel – a mouse heart is about 1,000th the size of a human heart.
So, the equipment must be sensitive, accurate and fast.
The team is working
to acquire and display data so that particular measurements of a pumping heart
can be made and shown as two-dimensional movies. Berr developed software to create
computer images of hearts that illustrate the “ejection fraction”: the
efficiency of the heart in pumping out blood. Epstein improved on Berr’s
work, creating higher-resolution, color images that provide additional information:
the direction of movement of various points on the heart muscle.
One of
the questions Berr is exploring with French and Epstein is the effect that a small
heart attack has on the rest of the heart. Not only does the heart attack itself
kill and damage muscle tissue, but the gene expression of the muscle changes,
causing further loss of muscle function.
Another researcher, Chris Kramer,
associate professor of radiology and director of cardiac MRI for the U.Va. Health
System, is working on a related question. After a heart attack, the left ventricle,
which pumps the oxygenated blood to the rest of the body, remodels itself. Kramer
is trying to understand how the heart knows to change its shape.
The MRI
technology that Berr has adapted allows researchers to see differences in hearts
after heart attacks.
“What we’ve seen is that there are three
areas of impact – the immediate area, in which the tissue has been killed
outright; the adjacent area; and the area remote from the dead muscle tissue,”
said Wesley Gilson, a graduate student studying with Epstein and French.
Gilson
is measuring the impact of a heart attack on the motion of the nearby heart muscle
wall in genetically manipulated mice.
“Once we understand which genes
are involved,” Epstein said, “we can go on to develop targeted drugs
for use in humans.”
