"...it's a whole system that we didn't realize existed."
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: http://www.cff.org
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Journal
Cell