ABOUT THE GRANT

This project focuses on cystic fibrosis (CF), an inheritable disease, that causes the body to make abnormally sticky,
thick mucus in the lungs, digestive tract, and other areas of the body. It seeks to elucidate some of the molecular mechanisms
that might explain why children diagnosed early through newborn screening (NBS) have such wide variations in susceptibility to
respiratory infections, long-term outcomes, and responses to treatment. Surprisingly, some persons with CF are far more susceptible
to infections than others. Currently, care focuses on symptom improvement and prevention of complications. Treatment is generally
prescribed based on disease severity rather than targeting pathophysiologic mechanisms. Thus, NBS is essential for diagnosing CF,
but diagnosis alone does not ensure healthy outcomes in persons with CF. CF is considered a genetic (monogenic autosomal recessive)
disorder, although there are variations in disease presentation due to multiple genes influencing individual characteristics that remain
to be defined. However, NBS and medical genetics have not kept up with the implementation of new technologies. New technological
developments allow for more types of testing at a reasonable cost that can be considered for application to universal newborn
population screening. For example, specific DNA mutations in NBS can maximize detection and minimize recall rates. Functional
explanation of the specific DNA mutation significance remains a critical unmet need. To address this, we will elucidate the molecular
mechanisms that explain why children diagnosed early through NBS have such wide variations in susceptibility to respiratory infections,
long-term outcomes, and responses to treatment.

Thus, an assessment strategy that can identify pwCF at the greatest risk of worsening respiratory disease, which remains a major cause
of morbidity and mortality, is needed to reduce disease progression among individuals diagnosed through NBS. Here, we hypothesize that
underlying genetic factors modulate immune responses to control individual risk for exacerbations of lung disease. Next-generation genomic
analyses will be used to identify how long noncoding RNAs regulate the function of a group of immune cells in the blood, in response
to Pseudomonas aeruginosa (Pa) infection and thus lead to disease progression. We expect that our studies will help identify personalized
therapeutic targets to limit CF lung disease progression caused by chronic Pa infection.

Dr. Hara Levy is professor (CHS) in the Division of Pulmonology and Sleep Medicine. She serves as co-director of the American Family Children’s Hospital Pediatric Cystic Fibrosis Center. Levy’s professional activities are influenced by her work as a physician-scientist with a track record of National Institutes of Health (NIH) and sponsored research funding since 2003. Levy has also served as associate director of the Milwaukee Cystic Fibrosis (CF) Center, director of pulmonology research at Lurie Children’s Hospital and Stanley Manne Children’s Research Institute at Northwestern University, and as head of the Pediatric Pulmonary Division at National Jewish Health in Denver.

Levy is a pediatric pulmonologist with an interest in tailoring medical care to individual patients based on their genomic profile. In addition to patient care, she has spearheaded research initiatives focused on understanding the genomic basis of pulmonary disease.

Levy’s research is dedicated to characterizing the relationships among environmental and genetic factors that modify CF lung disease severity and that predict clinical course and therapeutic response. Levy’s recent publications highlight her collaborative strength in the epidemiology of CF, healthcare disparities, and genetics- and genomics-based assays of CF and CF newborn screening.