Clearing the air(way) in fight against CF

Researchers find that IFRD1 gene might be a key to treating cystic fibrosis lung disease.

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WINSTON-SALEM, N.C.—If a team of researchers at Wake Forest University Baptist Medical Center in North Carolina and Cincinnati Children's Hospital Medical Center in Ohio are right, drug discovery and development professionals may have a promising new pathway to explore in the treatment of cystic fibrosis lung disease, in the form of a gene known as IFRD1 that modifies the severity of such lung disease. There is some irony, of course, in the fact that many of the researchers who helped identify the gene are located in the heart of tobacco country.

A study by the researchers appeared online in late February in advance of its print publication in Nature, and it is said to be the first published study to search the entire genome looking for genes that modify the severity of cystic fibrosis lung disease.

Researchers analyzed the genetic makeup of nearly 3,000 cystic fibrosis patients and discovered that small genetic differences in a gene called IFRD1 correlate with lung disease severity. As they tried to determine how the gene might alter the course of cystic fibrosis-related lung disease, the researchers found that the protein encoded by IFRD1 is particularly abundant in a type of white blood cell called neutrophils, and that it regulates their function. Neutrophils are known to cause inflammatory damage to the airways of people with cystic fibrosis.

The researchers note that prior to the current study, IFRD1 was not really considered in looking for genetic modifiers of disease severity, although the gene had been linked to stress responses in muscle and other tissues.
"When we knocked out IFRD1 in the mouse model, the absence caused a delay in the bacteria being cleared out—which is a problem of course—but it also resulted in a reduction in inflammation," notes Dr. Carl Langefeld, a study co-author and Wake Forest University School of Medicine researcher. "So understanding that element alone and the dual nature of the gene is quite important. If you can figure out what aspect of the gene or the proteins reduces inflammation without reducing bacterial clearance, or if this helps us search for alternative means of clearing bacteria, those are potentially valuable directions for future therapeutic work and translation to the bedside."

"What we see is that neutrophils are a double-edged sword in cystic fibrosis," adds Dr. Christopher Karp, senior investigator for the study and director of molecular immunology at Cincinnati Children's Hospital Medical Center. "It plays some role in protecting against bacteria in the airways but also destroys cells in the airway over time."

In addition to their other work, the researchers studied blood samples from healthy human volunteers to verify the impact of genetic differences in IFRD1 on neutrophil regulation. They found that the same IFRD1 variations that modified cystic fibrosis lung disease severity also altered neutrophil function in the healthy volunteers.

The investigators also determined that IFRD1's regulation of neutrophil function depends on its interaction with histone deacetylases—enzymes that are important for regulating gene transcription.

Karp stresses, however, that additional research is necessary to better understand this interaction and to find out what other genes and proteins IFRD1 interacts with—all with the goal in mind of finding out how they are connected to inflammation in cystic fibrosis lung disease.

"This certainly wasn't a gene that was on the radar for neutrophil function or cystic fibrosis lung disease," Karp notes. "And I think that points to the real benefit of these genome-wide scans. It may not be the gene per se that you pick up but more importantly the pathway. In this case, we have some renewed attention on the neutrophil regulation pathway and the potential for effective therapeutics that could come out of gaining greater knowledge of and control over that pathway."
"This is a good example of researchers with different expertise coming together and using the knowledge gained from mapping the human genome to make discoveries that improve our understanding of cystic fibrosis," adds Langefeld. "It may also help in the identification of targets for drug development and the development of tools for the earlier diagnosis of individuals with cystic fibrosis who are susceptible to severe lung disease."
According to the National Cystic Fibrosis Foundation, cystic fibrosis affects some 30,000 children and adults in the United States and 70,000 worldwide.
The defect in the CFTR gene causes the body to produce unusually thick, sticky mucus that clogs the lungs and leads to life-threatening lung infections. It also obstructs the pancreas and stops natural enzymes from helping the body break down and absorb food, but lung damage is the single biggest cause of morbidity and mortality.
Funding support for the study came from the National Cystic Fibrosis Foundation, the National Heart, Lung and Blood Institute, the Austrian Science Fund, and the Wake Forest University Health Sciences Center for Public Health Genomics.

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