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1st appeared
21
April 2000
Immune System Genes May be Targets for New Asthma Treatment Three potent proteins of the immune system, evolved to purge us of intestinal parasites, now often launch misguided attacks in our airways, triggering the congestion of asthma that leaves millions gasping for air. By studying the genetic machinery that controls production of these immune soldiers called cytokines, a team of scientists has demonstrated a potential strategy to silence their misfiring and quell the asthma response. In back-to-back papers in April and May, researchers at UCSF and the Lawrence Berkeley National Laboratory (LBL) report that a stretch of DNA controlling all three cytokine genes is so similar in humans and mice that the mouse DNA can activate the three human genes inserted in a mouse. The researchers showed too that the activity of all three genes can be at least partially blocked, suggesting that a single drug could be used to attack asthma at its genetic source. Such a drug could be reliably tested in mice, their study shows. "The primary aim of our research has been to demonstrate that if non-coding regions of DNA (stretches containing no genes) have been conserved in species separated by many millions of years, they probably perform vital functions," said Richard Locksley, MD, investigator in the Howard Hughes Medical Institute and professor of medicine and microbiology/ immunology at UCSF. "But in choosing a DNA region that modulates the genes for the cytokines IL-4, 5 and 13, we are dealing with genes that are dramatically expressed in asthma and other allergic diseases. Our experiments show that all three genes are regulated by the same non-coding DNA region, and interruption of this control affects all three genes at once. By blocking the activity of this region, we should be able to block the expression of all three genes." Many drugs are now being designed to interfere with activity of a single gene or the protein coded by that gene, but developing a drug to treat a disease caused by at least three genes could be far more difficult, Locksley said. Targeting a region of the genome that controls expression of the three genes at once may offer a solution. The demonstration that the human genes for IL-4, 5 and 13 can be faithfully expressed in mice under the regulation of the mouse DNA is being published in the May issue of the Journal of Immunology. Lead author is Dee A. Lacy, MD, PhD, research associate in the Howard Hughes Medical Institute at UCSF; senior author is Richard Locksley. Scientists at LBL collaborated on the research and the paper. The publication comes a few weeks after the team, led by the LBL scientists, identified the high degree of similarity between the mouse and human stretches of DNA that regulate expression of the genes. These findings were published in the April 7 issue of the journal Science. Over the past decade a powerful principle has emerged that genes shared by evolutionarily distant species are likely to play major roles for the organisms and may provide a window to understand basic genetic mechanisms. The research by the UCSF/LBL team extends that principle to the non-gene portions of the genome. "If evolution conserved a sequence over the 70 to 90 million years since mice and humans diverged, it likely has a function," says geneticist Kelly Frazer, PhD, senior scientist at LBL’s Life Sciences Division, senior author on the Science paper and co-author on the immunology paper. "Whether its function is to determine the structure of a protein coded for by a gene or to regulate gene expression, we should be able to identify these sequences though mouse-to-human sequence comparisons." Links: Source: Wallace Ravven, News Services |
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