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The role of glutathione S-transferase Pi (GSTPi) in asthma

Schroer, Kathy T.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1267721309

Abstract Details

2010, PhD, University of Cincinnati, Medicine : Molecular and Developmental Biology.
In the United States, over 30 million Americans suffer from asthma. More than 9 million of these asthmatics are children. Asthma is a complex genetic disease involving a multifaceted relationship between genetic background and environmental exposures. Among those genes consistently linked to asthma are the glutathione S-transferase (GST) family of genes, a group of phase II detoxification enzymes and redox regulators responsible for host defense against many environmental toxins and reactive oxygen species (ROS) including those found associated with diesel exhaust particles (DEP), environmental tobacco smoke (ETS), and mold. GSTPi is the predominant GST enzyme expressed in the lung. Many epidemiological studies have implicated a single nucleotide polymorphism in the GSTPi gene, GSTP1 Ile105Val (rs1695), as a predictor for asthma. While evidence supports a strong role for GSTPi in allergic airway disease, very little is known about the regulation of GSTPi in asthma and its contribution to oxidative stress in asthma. The studies in this dissertation focus on determining GST activity regulation during allergic inflammation and how it contributes to the development of asthma. We demonstrate that children in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort (N=570) carrying the GSTP1 Val105 allele, an allele associated with decreased GST enzyme activity, are significantly likely to wheeze when exposed to DEP, ETS, or mold. Exposure to multiple allergens increased the risk for wheezing independently of the GSTP1 genotype, suggesting that multiple environmental exposures can overwhelm the genetic effect. In order to address the regulation of GSTPi expression and total GST activity, we utilized mouse models of asthma. We demonstrate that allergen or interleukin 13 (IL-13) treatment attenuates GSTPi expression and total GST activity in the lung, although IL-13 is not required for this down-regulation. In addition, these studies demonstrate that IL-13 induced and not allergen induced attenuation of GSTPi expression and total GST activity is dependent on signal transducer and activator of transcription 6 (STAT6), suggesting that down-regulation of GSTPi expression and total GST activity can occur by STAT6 dependent and independent pathways. In addition, data suggests that down-regulation of GSTPi activity following allergen treatment may result in a decreased ability to neutralize oxidative stress intermediates and consequently, contribute to the asthma phenotype. The studies presented in this dissertation provide evidence that GSTPi expression and GST activity are regulated in asthma and warrant further study as a potential therapeutic target for asthma, especially asthma exacerbated by oxidative stress.
Gurjit Hershey, MD, PhD (Committee Chair)
Chris Karp, MD (Committee Member)
Robert Kahn, MD, MPH (Committee Member)
Timothy Lecras, PhD (Committee Member)
Fred Finkelman, MD (Committee Member)
129 p.
Molecular Biology
Asthma; GSTPi; GSTP1; environmental exposure; oxidative stress; reactive oxygen species

Recommended Citations

Citations

  • Schroer, K. T. (2010). The role of glutathione S-transferase Pi (GSTPi) in asthma [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1267721309

    APA Style (7th edition)

  • Schroer, Kathy. The role of glutathione S-transferase Pi (GSTPi) in asthma. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1267721309.

    MLA Style (8th edition)

  • Schroer, Kathy. "The role of glutathione S-transferase Pi (GSTPi) in asthma." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1267721309

    Chicago Manual of Style (17th edition)

ucin1267721309
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