Steven Kleeberger, Ph.D.
Immunity, Inflammation, and Disease Laboratory / Environmental Genetics Group
Building 101, Room D242
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Interaction between genetic background and exposures to environmental stimuli, and understanding the mechanisms through which environmental exposure interact with susceptibility genes, are critical to disease prevention. The EGG focuses on the role of genetic background in susceptibility to pulmonary effects of environmental stimuli. We integrate inbred mouse and cell-based models with haplotype association mapping (genetic), global gene expression analyses (genomic), and expression quantitative trait locus mapping (eQTL) to identify candidate susceptibility genes and gene networks. These and existent gene candidates are evaluated mechanistically in models using a battery of tools and approaches. The primary goal of these investigations is to determine whether homologues of the genes associate with disease risk in humans populations. Efforts to identify and validate susceptibility genes in mouse models of environmental disease will translate to identification of susceptible individuals and may lead to disease prevention strategies.
Project 1. Ozone (O3) is a major component of air pollution and it has important detrimental health effects on humans. Moreover, as much as 40% of the U.S. population is estimated to be exposed to potentially harmful levels of O3. We previously identified significant linkage of O3-induced lung hyperpermeability and inflammation QTLs to chromosomes 4 and 17 (Inf2), respectively. Ongoing research in the EGG has addressed the hypotheses that gene(s) within the chromosome 4 QTL [e.g. toll-like receptor 4 (Tlr4)] and Inf2 [e.g. tumor necrosis factor alpha (Tnf)] modulate differential susceptibility to O3-induced injury and inflammation.
Project 2. Reactive oxygen species (ROS) have been implicated in the pathogenesis of many acute and chronic clinical disorders such as acute lung injury, bronchopulmonary dysplasia (BPD), and cancer. The transcription factor NF-E2, related factor 2 (Nrf2) was identified as a candidate susceptibility gene for hyperoxia-induced lung injury and inflammation in adult inbred mice. The EGG investigates mechanisms through which Nrf2 modulates oxidant-induced lung injury in mice and humans. Through the Director's Challenge Program, and in collaboration with Drs. Doug Bell (NIEHS), Ben Van Houten (Univ Pittsburgh), Fernando Polack (Vanderbilt Univ), and Clare Weinberg (NIEHS), we also developed an integrated genetic and genomic program in inbred mice and a human population to identify factors that determine susceptibility to hyperoxia-induced lung disease in very low birth weight infants, including BPD.
Project 3. Respiratory syncytial virus (RSV) is the primary cause for hospitalization during the first year of life, and is the leading cause of bronchiolitis, pneumonia, mechanical ventilation and respiratory failure in infants worldwide. This project uses inbred mice and cell models to identify mechanisms of susceptibility to RSV infection and disease severity, and uses genetic information to determine whether functional polymorphisms in candidate genes associate with RSV disease severity in humans. Aims are 1) utilize genetic and genomic approaches to identify candidate susceptibility genes for RSV infection and disease in inbred mice and HapMap lymphoblastoid cell lines; 2) utilize gene targeting and overexpression to address in vivo functional roles of candidate genes in RSV disease pathogenesis; 3) evaluate roles of candidate gene polymorphisms in a population of children with RSV disease.
Steven R. Kleeberger, Ph.D., is head of the Environmental Genetics Group and the Oxidative Stress Mechanisms & Clinical Effects Group. He earned an A.B. at Miami University (Oxford, OH), and a Ph.D. at Kent State University (Kent, OH). He is Adjunct Professor at Duke University and the University of North Carolina. He has published over 160 peer-reviewed articles and two dozen book chapters and invited reviews. Dr. Kleeberger was professor of environmental health sciences at Johns Hopkins University before joining NIEHS (2002). He was Chief of the Laboratory of Respiratory of Biology (2002-2010), and Acting Deputy Director of NIEHS (2009-2011). Dr. Kleeberger has given over 100 invited lectures worldwide. He served on multiple study sections at the NIH, advisory committees on genetic susceptibility, and EPA Clean Air Scientific Advisory Committee Review Panels. His research utilizes genetic and genomic approaches to identify susceptibility genes for environmental lung disease.
Cho HY, van Houten B, Wang X, Miller-DeGraff L, Fostel J, Gladwell W, Perrow L, Panduri V, Kobzik L, Yamamoto M, Bell DA, Kleeberger SR. Targeted deletion of nrf2 impairs lung development and oxidant injury in neonatal mice. Antioxid Redox Signal. 2012;17(8):1066-82.
Verhein KC, McCaw Z, Gladwell W, Trivedi S, Bushel PR, Kleeberger SR. Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice. Environ Health Perspect. 2015;123(8):799-805.
Cho HY, Imani F, Miller-DeGraff L, Walters D, Melendi GA, Yamamoto M, Polack FP, Kleeberger SR. Antiviral activity of Nrf2 in a murine model of respiratory syncytial virus disease. Am J Respir Crit Care Med. 2009;179(2):138-50.
Nichols JL, Gladwell W, Verhein KC, Cho HY, Wess J, Suzuki O, Wiltshire T, Kleeberger SR. Genome-wide association mapping of acute lung injury in neonatal inbred mice. FASEB J. 2014;28(6):2538-50.
Caballero MT, Serra ME, Acosta PL, Marzec J, Gibbons L, Salim M, Rodriguez A, Reynaldi A, Garcia A, Bado D, Buchholz UJ, Hijano DR, Coviello S, Newcomb D, Bellabarba M, Ferolla FM, Libster R, Berenstein A, Siniawaski S, Blumetti V, Echavarria M, Pinto L, Lawrence A, Ossorio MF, Grosman A, Mateu CG, Bayle C, Dericco A, Pellegrini M, Igarza I, Repetto HA, Grimaldi LA, Gudapati P, Polack NR, Althabe F, Shi M, Ferrero F, Bergel E, Stein RT, Peebles RS, Boothby M, Kleeberger SR, Polack FP. TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization. J Clin Invest. 2015;125(2):571-82.