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Environmental Factor, August 2015

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NIEHS environmental genetics leader speaks at Texas research center

By Greg Buchold

Steve Kleeberger

"No one responds the same way to the same stimulus, in terms of environmental exposures,” Kleeberger said in the CTEHR podcast. “Understanding those factors that contribute to individual response is really key.” (Photo courtesy of Steve McCaw)

Steven Kleeberger, Ph.D., presented a June 17 mentoring seminar at the Texas A&M University Center for Translational Environmental Health Research (CTEHR). Headed by Cheryl Walker, Ph.D., CTEHR is one the newer Environmental Health Sciences Core Centers funded by the institute’s Division of Extramural Research and Training (see sidebar).

Environmental contributors to lung disease

Kleeberger, head of the NIEHS Environmental Genetics Group, discussed ”Susceptibility to Environmental Lung Disease: Contributions from the Nuclear and Mitochondrial Genomes.”

He focused on three recent advances in his laboratory’s multidisciplinary approach to understanding environmental lung disease.

The first advance involved a translational collaboration with the Infant Foundation in Argentina that identified a genetic variation, or single nucleotide polymorphism (SNP), in humans that enhances respiratory syncytial virus (RSV) disease in children. This SNP is comparable to one that Kleeberger and his team discovered in a similar gene in mice, which codes for an immune response. The human SNP enhances lung inflammation and disease, producing effects similar to those found when researchers disrupted the gene in mice.

Second, in a study of children in Buenos Aires, Argentina, Kleeberger and his collaborators examined loss-of-function mutations in a gene involved in immune function, known as toll-like receptor 4. These mutations dramatically worsened responses to a bacterial endotoxin in children from high socioeconomic status (SES) households, but they were surprisingly protective in lower SES populations (see story).

A third study used ultra-deep sequencing methods to detect genetic variations in the mitochondrial genome of inbred mouse strains. The researchers identified a variety of novel mitochondrial targets that appear to affect susceptibility to a disorder known as bronchopulmonary dysplasia, which occurs in premature infants receiving oxygen therapy for underdeveloped lungs and lung infections (see summary).

Kleeberger enjoyed interacting with students at the breakfast and seminar, hosted by the Career Development Program. “One of the high points of the visit was meeting with the students, fellows, and faculty members,” Kleeberger said. “What an enthusiastic and interesting group! It was great to talk with them about their science.”

Citations: 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. 2015. TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization. J Clin Invest 125(2):571-582.

Nichols JL, Gladwell W, Verhein KC, Cho HY, Wess J, Suzuki O, Wiltshire T, Kleeberger SR. 2014. Genome-wide associated mapping of acute lung injury in neonatal inbred mice. FASEB J 28(6):2538-2550.

(Greg Buchold, Ph.D., is a former NIEHS postdoctoral fellow in the Reproductive and Developmental Biology Laboratory.)

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