Hara Levy, MD, MMSc
Children’s Hospital of Wisconsin
Assistant Professor of Pediatrics
Medical College of Wisconsin
Children’s Research Institute
(414) 955-2379 | Fax: (414) 266-6742
Integrating Genetics and Genomics
The Levy lab focuses on integrating genetic and genomics to advance the understanding of the contribution of environmental, genetic, and epigenetic factors influencing the progression of cystic fibrosis (CF) lung disease. An understanding of the link between the CFTR gene defect, responsible for CF, and functional impairment that leads to clinical sequelae should help in the development of cellular and molecular markers that are easily measured and predictive of therapeutic efficacy such as the restoration of the host defense function. This would allow for a direct link between gene expression and functional correlation applicable in CF and also more common chronic inflammatory lung diseases.
Currently, we are using the samples from the Wisconsin newborn screening project, as well as additional clinical samples from patients followed clinically at our CF centers, to identify non-invasive gene expression markers for CF by generating a genome-wide expression profile of serum samples from CF patients over time, thereby defining a unique expression signature as it correlates to infection status and lung function. Therefore, our research is helping to generate a unique molecular signature and associated risk established early in life providing unprecedented opportunity for novel prognostic and therapeutic interventions in CF and perhaps a model for other chronic inflammatory lung diseases.
Our studies further identify an innovative assay which could potentially define a pathogen specific response, provide data associated with disease phenotypes and support the use of an integrated approach to move beyond marker identification to mechanism discovery. Further, utilizing these microarray studies from our laboratory, we have confirmed the ability to use this technology for the identification of molecular signatures that track with genotype and clinical phenotype. Through this application, we have begun to harness the functional genomics infrastructure to longitudinally dissect molecular events in CF in response to infection status and integrate with genotyping in a manner not previously possible.
Our future goals include identification of a series of non-CFTR candidate genes through integration of functional genomics and genetics that may impact the severity of CF lung disease and account for phenotypic heterogeneity. We hope to further the development of a highly accurate, cost effective global gene expression profiling in CF that is sufficiently sensitive to address discrete biologic questions utilizing the integration of genomics and genetics.
Ly NP, Ruiz-Pérez B, Onderdonk A, Tzianabos AO, Litonjua AA, Liang C, Laskey D, Delaney ML, DuBois AM, Levy H, Gold DR, Ryan LM, Weiss ST, Celedón JC. Mode of delivery and cord blood cytokines: a birth cohort study. Clin Mol Allergy 2006;4:13. PMID: 17002791.
Levy H, Kalish LA, Huntington I, Weller N, Gerard C, Silverman EK, Celedón JC, Pier GB, Weiss ST. Inflammatory markers of lung disease in adult patients with cystic fibrosis. Pediatr Pulmonol 2007;42(3):256-62. PMID: 17245735.
Levy H, Kalish LA, Cannon CL, García KC, Gerard C, Goldmann D, Pier GB, Weiss ST, Colin AA. Predictors of Mucoid Pseudomonas Colonization in Cystic Fibrosis Patients. Pediatr Pulmonol 2008; 43(5):463-71. PMID: 18361452.
Levy H, Murphy AJ, Zou F, Gerard C, Klanderman BJ, Schuemann B, Lazarus R, García KC, Celedón JC, Drumm M, Dahmer MK, Quasney MW, Schneck K, Reske M, Knowles MR, Pier GB, Lange C, Weiss ST. IL1-β polymorphisms modulate cystic fibrosis lung disease. Pediatr Pulmonol 2009; 44 (6): 580-593. PMID: 19431193.
Jadin SA, Wu GS, Zhang Z, Shoff SM, Tippets BM, Farrell PM, Miller T, Rock MJ, Levy H and Lai, HJ. Growth and pulmonary outcomes during the first two years of life of breastfed and formula-fed infants diagnosed with cystic fibrosis through the Wisconsin Routine Newborn Screening Program. The American Journal of Clinical Nutrition. May;93(5):1038-47. Epub 2011 Mar 23. PMID: 21430114.
Rock M J, Levy H, Zaleski C, Farrell P M. Factors Accounting for a Missed Diagnosis of Cystic Fibrosis After Newborn Screening. Pediatr Pulmonol. 2011; 46(12):1166-74. PMID: 22081556.
Baughn JM, Quasney MW, Simpson P, Merchant D, Li SH, Levy H, Dahmer MK. Association of CFTR Gene Variants with Acute Lung Injury in African American Children with Pneumonia. Critical Care Medicine. 2012; 40(11):3042-9. PMID: 22890249. PMCID pending.
Sebro R*, Levy H*, Schneck K, Dimmock, D, Raby BA, Cannon, CL, Broeckel U and Risch NJ. Cystic Fibrosis mutations for F508del compound heterozygotes predict sweat chloride levels and pancreatic sufficiency. Clin Genet. 2012 Dec; 82(6):546-51. PMID: 22035343 (* indicates co-first authorship).
Levy H, Wang X, Kaldunski M, Jia S, Kramer J, Pavletich SJ, Reske M, Gessel T, Yassai M, Quasney MW Dahmer MK, Gorski J, Hessner MJ. Transcriptional signatures as a disease specific and predictive inflammatory biomarker. Genes and Immunity. 2012 Dec; 13(8):593-604. PMID: 22972474. PMCID Pending.
Children’s Research Institute Ann Hardy Fund
Peer Review (funded)
NIH/Office of the Director: “Integration of Genomics with Genetics-Molecular Phenotypes for CF Lung Disease” Principal Investigator
NIH/NHLBI: “IL-1 Family Gene polymorphisms and Susceptibility to P. aeruginosa in CF Patients”
NIH/NHLBI: “Pulmonary Benefits of Cystic Fibrosis Neonatal Screening”
Subcontract Principal Investigator (PI: Philip M. Farrell, PhD)
NIH/NIDDK: “ Malnutrition and Lung Disease in Cystic Fibrosis”
Co-Principal Investigator (PI: HJ Lai, PhD)
Juvenile Diabetes Research Foundation: “Serum Induced Transcriptional Signature in T1DM and its Relationship to CFDM”
Co-Investigator (PI: Martin Hessner, PhD)
Peer Review (council review)
NIDDK: “Efficacy of Tailored Family-Centered Genetic Counseling for Cystic Fibrosis” Co-Principal Investigator (PI: Audrey Tluczek PhD)
Melissa Reske, Research Associate