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September 28, 2000
MEDIA CONTACT: Marjorie Centofanti
PHONE: (410) 955-8725
E-MAIL: mcentofanti@jhmi.edu

Scientists Spot Way Around Cystic Fibrosis Cells' Poor Performance, Way To Improve Drug Testing

Exploiting what appears to be a newly found regulator of cystic fibrosis
chemistry, scientists at Johns Hopkins report they have been able to
experimentally improve the function of the cell molecule most affected by
this common inherited disorder.

Writing in the October edition of the journal Cell, the Hopkins team
described their discovery of a previously unknown system that helps control
the protein product made by the cystic fibrosis gene, called CFTR.

CFTR protein molecules shape themselves into channels in the cells that
line the lungs and other organ targets of cystic fibrosis, the most common
lethal genetic disease in Caucasians. Cystic fibrosis is a recessive
disorder marked by accumulation of mucus and by abnormal sweat, digestive
and other secretory glands.

At the biochemical level, the channels are a main way cells regulate the
flow of salts in and out of cells.  "People with cystic fibrosis have
abnormal chemistry outside of cells, not because their CFTR molecules won't
work, but largely because they have too few of them on their cell
membranes," says molecular biologist Min Li, Ph.D., who led the research team.

In the Hopkins study done on human tissues, human and mouse cell cultures
and isolated cell membranes, Li and his team showed that a regulatory cell
protein called CAP 70 lies adjacent to CFTR in cell membranes and binds to
CFTR as well.  Moreover, when CAP 70, also a protein, is present, it links
two CFTR molecules together, subtly changing the shape of each so they work
together more efficiently.  "This counters the decades-old idea that CFTR
exists only as single molecules," says Li.  "There's a whole control system
here we didn't know existed before."

Potentially, what this means is that in CF patients, existing channels
could be made to work more efficiently.  "We might be able to compensate
for their having too few of them," says Li.  In one part of their research,
for example, team members were able to double the flow of ions --charged
atoms --  through CFTR channels by adding CAP 70.

Beyond the potential for compensating for the disease's effect on target
cells, the new work should quickly lead to improved screening of CF
therapies, Li says.  The traditional way to spot a useful drug, for
example, has been a painstaking method isolating cell membranes and making
measurements of minuscule changes in current.  "But now that we know that
dimers --the double CFTR molecules --are the working version in cells, we
can screen for them, and they're far easier to detect," Li says.

"It's a myth in the public mind that as soon as you figure out the key gene
in a disease, you can stop worrying.  What we show here is that there's far
more operating than a single gene; it's far more complex."  The study, Li
says, is a classic example of the new direction research is taking now that
human genome studies are becoming routine --scientists are now avidly
studying how the products of genes interact.

Because CF is caused by an abnormal recessive gene, people with the disease
must inherit an abnormal gene from each parent.  One in every 31 Americans
carries a copy of the CFTR gene that's defective in some way, says Li.

The research was funded by grants from the NIH, the Cystic Fibrosis
Foundation and the American Heart Association.   Other scientists on the
team were Shusheng Wang, Ph.D., Hongwen Yue, Ph.D.,  Rachel B. Derin, B.S.,
and William B. Guggino, Ph.D.

Related Web sites: http://physiology.med.jhu.edu/min/min.html  for
information on Min Li's research.

For information on cystic fibrosis from the Cystic Fibrosis foundation:


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