University of Arizona researchers are launching an international consortium to determine if better regulation of a protein found in lung cells might impact persistence of asthma from childhood to adulthood, working toward personalized therapies for people with adult chronic asthma.
The consortium's larger goal is to stop asthma in childhood and continue work toward an overall cure for the disease.
Stefano Guerra, MD, PhD, MPH, a professor in the UA Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, received a $3.6 million, five-year grant from the National Institute of Allergy and Infectious Diseases, to study the protein CC16, a biomarker of injury to epithelial cells that line the lungs and are believed to be a protective mediator in the airway inflammatory process. The protein is produced mainly by "club cells," also known as "bronchiolar exocrine cells," in the outer airways of the lungs, but can be measured in blood circulation.
"The project establishes an international consortium among some of the world's leading asthma research groups that provide unique data on thousands of participants followed from birth well into their adult life," said Dr. Guerra.
These groups include the Tucson Children's Respiratory Study, launched in 1980 by the Arizona Respiratory Center (now the UA Health Sciences Asthma and Airway Disease Research Center), and Sweden's BAMSE (the Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) and the United Kingdom's Manchester Asthma and Allergy Study (MAAS). Each involve longitudinal research with observation of patients over decades.
"This study builds upon the already outstanding work on asthma-related research at the University of Arizona to move forward on treatments for a disease that is affecting the quality of so many lives, especially our children," said UA President Robert C. Robbins. "Personalized medicine is the future of health care, and the UA is recognized as a leader in this emerging and vitally important area. I am excited to learn what Dr. Guerra and his colleagues find."
Erik Melén, MD, PhD, with Sweden's Karolinska Institutet, and Angela Simpson, MD, PhD, MBChB, with the North West Lung Centre of England's University Hospital of South Manchester, are principal investigators of the BAMSE and MAAS cohorts, and will serve as co-investigators on Dr. Guerra's team.
"Participants from these research groups will be characterized in terms of their levels and changes over time of circulating CC16, with the hypothesis that individuals with persistent CC16 deficits are at increased risk for persistence of childhood asthma," Dr. Guerra said. The team also will test if protective mechanisms of CC16 are affected by responses to asthma pathogens by studying how nasal epithelial cells that will be collected from participants from these cohorts respond to Mycoplasma pneumoniae, a bacterium linked to asthma worsening and chronic asthma.
"Ultimately, our objective is to establish the value of CC16 as a protective factor from persistence of asthma (into adulthood) and evaluate its possible use in identifying which patients are at high risk and novel therapeutic interventions to help them," he said.
If these studies help determine CC16 deficits' role in persistent asthma, the next step would be to evaluate CC16 augmentation as a therapeutic intervention in this disease, by either administering the human recombinant CC16 protein (which already is being tested in airway diseases) or molecules that increase a body's internal production of CC16.
"For example, we recently reported that retinoids (chemical compounds that regulate epithelial cell growth) increase CC16 secretion by human bronchial epithelial cells and vitamin A treatment results in a significant increase of serum CC16 levels," Dr. Guerra said.
Persistent asthma in childhood is linked to other adult respiratory illnesses, such as chronic obstructive pulmonary disease, for which patients could benefit from this research, Dr. Guerra added. Dr. Guerra also is the Henry E. Dahlberg Chair in Asthma Research at the UA College of Medicine - Tucson, population science director with the UA Health Sciences Asthma and Airway Disease Research Center, an associate professor with the UA Mel and Enid Zuckerman College of Public Health and a UA BIO5 Institute member.
UA co-investigators on the grant include:
- Tara Carr, MD, assistant professor of medicine and surgery, director, Adult Allergy Program, PACCS, UA College of Medicine - Tucson, and UAHS Asthma and Airway Disease Research Center member;
- Marilyn Halonen, PhD, professor emerita, UA Department of Pharmacology, UA College of Medicine - Tucson, UAHS Asthma and Airway Disease Research Center and UA BIO5 member, and an immunologist with extensive expertise in biomarkers of lung disease (including CC16);
- Monica Kraft, MD, professor and chair of the UA Department of Medicine, the Robert and Irene Flynn Endowed Chair of Medicine at the UA College of Medicine - Tucson, UAHS Asthma and Airway Disease Research Center deputy director and UA BIO5 member;
- Julie Ledford, PhD, a UA research scientist, assistant professor of immunobiology and medicine, UA College of Medicine - Tucson, and UAHS Asthma and Airway Disease Research Center and UA BIO5 member;
- Fernando Martinez, MD, UAHS Asthma and Airway Disease Research Center director, the Swift-McNear Professor of Pediatrics, the Chalfont/Moore Chair on Respiratory Medicine, a UA Regents' Professor and member of UA BIO5 and the UA Genetics Graduate Interdisciplinary Program; and
- Duane Sherrill, PhD, professor emeritus, epidemiology and biostatistics division, UA Mel and Enid Zuckerman College of Public Health, and a leading expert in longitudinal modeling of pulmonary data.
More than 25 million - or one in 13 - Americans and 235 million people globally suffer from asthma, according to the U.S. Centers for Disease Control and Prevention and the World Health Organization. Levels of asthma include mild intermittent, mild persistent, moderate persistent and severe persistent asthma. These vary from fewer than two episodes a week with no problems between flare-ups to constant symptoms, frequent flare-ups and a marked decrease in physical activity allowed.
This research was supported by the National Institute of Allergy and Infectious Diseases, a unit of the National Institutes of Health, under grant No. 1R01AI135108-01.
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