The Levy lab focuses on integrating genetic and genomic analyses to advance our understanding of how environmental, genetic, and epigenetic factors influence the progression of cystic fibrosis (CF).
Our overall goal is to contribute to the development of personalized monitoring and treatment strategies for CF patients, particularly children. Our research employs cutting-edge technologies to generate molecular profiles of CF patients over time. We envision that our investigations will identify the molecules that provide the most disease-relevant information for individual patients and that generate the most meaningful, concrete links to clinical characteristics.
Integrating Genetics and Genomics to Understand CF Progression
We’re combining our work with our patients with cutting-edge laboratory technologies to achieve our vision of patient-centered care for children with cystic fibrosis (CF). For general information about CF, see our Resources information below.
Although CF is a monogenic autosomal recessive disorder caused by mutations in the gene encoding cystic fibrosis transmembrane regulator (CFTR), clinical heterogeneity causes diagnostic uncertainty, especially in infants without symptoms and in older patients with milder phenotypes. A variety of genetic, epigenetic, and environmental factors further complicate the evolution of CF in each patient. For example, infection with the Gram-negative pathogen Pseudomonas aeruginosa accounts for most of the morbidity and mortality associated with lung disease in CF; we suspect that a set of immune proteins contributes to the severity of CF lung disease by mediating innate immunity to P. aeruginosa infection. Other changes in gene expression occur in CF, affecting fluid and electrolyte transport, intracellular trafficking, and inflammation. Thus, CF arises from the activities of genes and proteins within a complex transcriptional and functional framework. Global analyses are therefore critical to monitoring gene and protein expression and to understanding the mechanisms underlying the extensive phenotypic heterogeneity of CF. In the Levy lab, we use a novel approach to generate genome-wide expression profiles of CF patients over time.
Genome-Wide Expression Profiles
We have harnessed data from CF newborn screening projects and from patients followed clinically at our CF center to establish a non-invasive strategy for constructing genome-wide expression profiles. We expose reporter cells to sera from CF patients sampled over time to generate dynamic genome-wide expression profiles with RNA quantitation/sequencing technologies. These measurements enable us to correlate clinical characteristics (such as P. aeruginosa infection and lung function) with gene expression in each unique patient. Additional molecular and cellular assays allow us to refine the mechanisms that underpin these changes in expression, and we are in the process of developing strategies to examine the expression of miRNAs and genes associated with single-nucleotide polymorphisms and/or copy-number variants. We anticipate that these investigations will highlight genes/proteins that define a patient’s clinical course and treatment response. Our clinical interests include establishing molecular definitions of disorders of the CF spectrum, such as CFTR-related diseases and CFTR-related metabolic syndrome , as well as exploring the impact of CFTR mutations on gene expression, predictors of lung-disease severity, newborn screening, and therapeutic responsiveness.
Taken together, our cutting-edge quantitative investigations will empower us to identify and characterize non-CFTR genes that may tune the severity of CF lung disease and account for the phenotypic heterogeneity that challenges physicians on a daily basis. Our pursuit of large-scale, epidemiological data from clinical cohorts allows us to evaluate the effect and impact of differential gene expression and the clinical relevance of these changes over the course of each patient’s life.
- Zainub Ashrafi, MS, Research Coordinator I
- Kate A. Woods, Research Coordinator
- Xi Zhang, Research Scientist
- Justin Ideozu, Postdoctoral Associate
- HuiChuan Lai, PhD, University of Wisconsin-Madison
- Marty Hessner, PhD, Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin
- Philip Farrell, MD, PhD, University of Wisconsin-Madison
- DB Sanders, MD, University of Wisconsin-Madison
- Pippa Simpson, PhD, Quantitative Heath Sciences, Department of Pediatrics, Children’s Hospital of Wisconsin
- Uli Broeckel, PhD, Individualized Medicine Institute, Department of Pediatrics, Children’s Hospital of Wisconsin
- Children's Hospital of Wisconsin
- Medical College of Wisconsin Department of Pediatrics, Divisions of Pulmonary and Critical Care Medicine
Hara Levy, MD, a pediatric pulmonologist who specializes in lung disease, particularly cystic fibrosis, joined Lurie Children’s and Northwestern University Feinberg School of Medicine in March 2015 as the Research Director for the Division of Pulmonary Medicine at Lurie Children’s and as Associate Professor of Pediatrics at the Feinberg School.
Dr. Levy’s laboratory is located in the Human Molecular Genetics Program at Stanley Manne Children’s Research Institute, and her research focuses on understanding the influence of environmental, genetic and epigenetic factors on the progression of cystic fibrosis lung disease. Dr. Levy comes to us from the Children’s Hospital of Wisconsin and the Medical College of Wisconsin .
List of publications indexed in PubMed by the Levy Laboratory.
- Ren CL, Borowitz DS, Gonska T, Howenstine MS, Levy H, Massie J, Milla C, Munck A, Southern KW. Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis. J Pediatr. 2017 Feb;181S:S45-S51.e1. doi: 10.1016/j.jpeds.2016.09.066. PMID: 28129812
- Levy H, Nugent M, Schneck K, Stachiw-Hietpas D, Laxova A, Lakser O, Rock M, Dahmer MK, Biller J, Nasr SZ, Baker M, McColley SA, Simpson P, Farrell PM. Refining the continuum of CFTR-associated disorders in the era of newborn screening. Clin Genet. 2016 May;89(5):539-49. doi: 10.1111/cge.12711. Epub 2016 Jan 20. PMID: 26671754 Free PMC Article
- Corvol H, Blackman SM, Boëlle PY, Gallins PJ, Pace RG, Stonebraker JR, Accurso FJ, Clement A, Collaco JM, Dang H, Dang AT, Franca A, Gong J, Guillot L, Keenan K, Li W, Lin F, Patrone MV, Raraigh KS, Sun L, Zhou YH, O'Neal WK, Sontag MK, Levy H, Durie PR, Rommens JM, Drumm ML, Wright FA, Strug LJ, Cutting GR, Knowles MR. Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. Nat Commun. 2015 Sep 29;6:8382. doi: 10.1038/ncomms9382. PMID: 26417704 Free PMC Article
- Parker-McGill K, Nugent M, Bersie R, Hoffman G, Rock M, Baker M, Farrell PM, Simpson P, Levy H. Changing incidence of cystic fibrosis in Wisconsin, USA. Pediatr Pulmonol. 2015 Nov;50(11):1065-1072. doi: 10.1002/ppul.23265. Epub 2015 Aug 10. PMID: 26258862 Free PMC Article
- Levy H, Farrell PM. New challenges in the diagnosis and management of cystic fibrosis. J Pediatr. 2015 Jun;166(6):1337-41. doi: 10.1016/j.jpeds.2015.03.042. No abstract available. PMID: 26008169 Free PMC Article
- Miller MR, Soave D, Li W, Gong J, Pace RG, Boëlle PY, Cutting GR, Drumm ML, Knowles MR, Sun L, Rommens JM, Accurso F, Durie PR, Corvol H, Levy H, Sontag MK, Strug LJ. Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis. J Pediatr. 2015 May;166(5):1152-1157.e6. doi: 10.1016/j.jpeds.2015.01.044. Epub 2015 Mar 11. PMID: 25771386 Free PMC Article