WINSTON-SALEM, N.C.—In a bit of irony, researchers at Wake Forest University Baptist Medical Center—based in the midst of tobacco country—may have been instrumental in finding the key to treating a thorny lung disease problem.
Specifically, the Wake Forest team and their colleagues elsewhere have identified a gene that modifies the severity of lung disease in people with the lethal genetic condition known as cystic fibrosis, and this research could open the door to possible new targets for treatment.
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.
"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," says Dr. Carl Langefeld, a study co-author and Wake Forest University School of Medicine researcher. "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."
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.
"Neutrophils appear to be particularly bad actors in cystic fibrosis," notes senior investigator Dr. Christopher Karp, director of Molecular Immunology at Cincinnati Children's Hospital Medical Center. "They are important to the immune system's response to bacterial infection. In cystic fibrosis, however, neutrophilic airway inflammation is dysregulated, eventually destroying the lung."
Wake Forest notes that prior to the current study, IFRD1 was not really considered by researchers looking for genetic modifiers of disease severity, although the gene had been linked to stress responses in muscle and other tissues. To further explore IFRD1's role in the disease process, the researchers studied mice in which the IFRD1 gene was removed. Deleting the gene confirmed its role in regulating inflammation and disease. While the absence resulted in delayed clearance of bacteria from the airway, it also resulted in less inflammation and disease.
The researchers also 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.
Although this still is a long way off from identifying a new therapy, what does serve as a promising springboard for novel treatments is that fact that 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.
The researchers stress, however, that additional research is necessary to better understand this interaction before its potential role for treatment can be known.
"It's possible that IFRD1 itself could become a target for treatment, but right now it's a signpost to pathways for further study," Karp says. "We want to find out what other genes and proteins IFRD1 interacts with, and how this is connected to inflammation in cystic fibrosis 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.
Attacking a root cause of the lung damage from a genomic or proteomic angle would be a vast improvement over some of the other potential strategies proposed in recent research, such as an October 2007 study suggesting that long-term high-dose ibuprofen could slow the rate of decline in lung function in children when treatment is started under the age of 13. Also, a more recent study out of Heidelberg, Germany, this February had researchers preventing cystic fibrosis lung disease in a mouse model by spraying amiloride into the lungs.
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.
Specifically, the Wake Forest team and their colleagues elsewhere have identified a gene that modifies the severity of lung disease in people with the lethal genetic condition known as cystic fibrosis, and this research could open the door to possible new targets for treatment.
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.
"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," says Dr. Carl Langefeld, a study co-author and Wake Forest University School of Medicine researcher. "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."
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.
"Neutrophils appear to be particularly bad actors in cystic fibrosis," notes senior investigator Dr. Christopher Karp, director of Molecular Immunology at Cincinnati Children's Hospital Medical Center. "They are important to the immune system's response to bacterial infection. In cystic fibrosis, however, neutrophilic airway inflammation is dysregulated, eventually destroying the lung."
Wake Forest notes that prior to the current study, IFRD1 was not really considered by researchers looking for genetic modifiers of disease severity, although the gene had been linked to stress responses in muscle and other tissues. To further explore IFRD1's role in the disease process, the researchers studied mice in which the IFRD1 gene was removed. Deleting the gene confirmed its role in regulating inflammation and disease. While the absence resulted in delayed clearance of bacteria from the airway, it also resulted in less inflammation and disease.
The researchers also 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.
Although this still is a long way off from identifying a new therapy, what does serve as a promising springboard for novel treatments is that fact that 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.
The researchers stress, however, that additional research is necessary to better understand this interaction before its potential role for treatment can be known.
"It's possible that IFRD1 itself could become a target for treatment, but right now it's a signpost to pathways for further study," Karp says. "We want to find out what other genes and proteins IFRD1 interacts with, and how this is connected to inflammation in cystic fibrosis 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.
Attacking a root cause of the lung damage from a genomic or proteomic angle would be a vast improvement over some of the other potential strategies proposed in recent research, such as an October 2007 study suggesting that long-term high-dose ibuprofen could slow the rate of decline in lung function in children when treatment is started under the age of 13. Also, a more recent study out of Heidelberg, Germany, this February had researchers preventing cystic fibrosis lung disease in a mouse model by spraying amiloride into the lungs.
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.
