<p>The work in this thesis encompasses (a) the development of a robust analytical method suitable for the comprehensive analysis of polar and non-polar metabolites in a single analysis and (b) the application of this method to the study of the metabolites involved in peanut allergy. During the course of this work the methods for the analysis of large metabolite data sets evolved significantly and the approaches used in this work evolved in parallel to the literature. This work constitutes the first comprehensive metabolomic investigation of an allergy response.</p> <p>Hypersensitivity or allergy to peanuts is an increasingly problematic health concern around the world involving approximately 1-2% of children in North America. There are no useful clinical biomarkers for this allergy. Comprehensive metabolomics holds vast potential for the discovery of metabolites and metabolite pathways that may be involved during the development of peanut allergy and during peanut-induced anaphylaxis. The comprehensive study of metabolites involved in peanut allergy presented a significant challenge since no single analytical technique is capable of analysis of all metabolites within a single analytical run.</p> <p>The thesis begins with development of a tandem column liquid chromatography-electrospray ionization-mass spectrometry method which allowed the separation and analysis of both polar and non-polar metabolites in a single analysis. This tandem column technique was also shown to significantly reduce the amount of ion suppression observed compared to the ion suppression observed when using either column independently.</p> <p>This methodology was applied to the comprehensive metabolomics analysis of blood serum samples obtained from mice which were (a) being sensitized to peanuts and (b) undergoing anaphylaxis. This analysis discovered a profound impact on metabolites involved with purine metabolism, resulting in an elevation of uric acid levels. This discovery led to further investigations which confirmed that uric acid is essential for peanut sensitization in mice. This discovery was only possible due to the use of a comprehensive metabolomics approach.</p> <p>The analytical methodology was then applied to the study of metabolomic changes in sensitized mice as they experienced peanut-induced anaphylaxis. A number of metabolomic changes including taurine level elevation were correlated with peanut-induced anaphylaxis. Finally, a serendipitous opportunity arose to analyze blood serum samples from peanut allergic children that had undergone an oral peanut challenge. The comprehensive metabolomic study of these samples revealed massive changes in their serum metabolomes as a result of peanut exposure. A number of lipids and lysophospho-lipids were shown to have increased dramatically and may represent novel biomarker candidates for peanut-induced anaphylaxis in humans.</p> <p>In summary, this thesis had demonstrated that comprehensive metabolomic analyses can be successfully applied to complex syndromes such as peanut allergy and yield useful mechanistic and clinical insights to this disorder.</p> / Doctor of Philosophy (PhD)

<p>Tropospheric fine particulate matter (PM) poses serious health risks and has a significant impact on global climate change. The measurement of various aspects of PM is challenging due to its complex chemical nature. This dissertation addresses various aspects of PM, including composition, measurement, and visibility. The U.S. Environmental Protection Agency (EPA) proposed a new secondary standard based on visibility in urban areas using 24-h averaged measurements of either light scatter or PM concentration. However shorter averaging times may better represent human perception of visibility. Data from two studies conducted in Lindon, UT, 2012, and Rubidoux, CA, 2003, were used to compare different techniques to estimate visibility, particularly the effect of relative humidity on visibility estimations. Particle composition was measured in Salt Lake City during January-February of 2009. One-hour averaged concentrations of several gas phase and particle phase inorganic species were measured. The results indicate ammonium nitrate averages 40% of the total PM2.5 mass in the absence of inversions and up to 69% during strong inversions. Also, the formation of ammonium nitrate is nitric acid limited, while the formation of ozone appears to be oxidant and volatile organic carbon (VOC) limited. Reduction of NOx will reduce ammonium nitrate secondary particle formation, however, a decrease in NOx may increase ozone concentration. </p><p> Due to the complexity of PM it is poorly characterized. A large fraction of PM is composed of organic compounds, but these compounds are not regularly monitored due to limitations in current sampling techniques. The GC-MS Organic Aerosol Monitor (OAM) combines a collection device with thermal desorption, gas chromatography and mass spectrometry to quantitatively measure the carbonaceous components of PM on an hourly averaged basis. A compact GC and simple pre-concentrator were developed for the system to decouple separation from manual injection and enhance separation of environmentally-relevant polar organic compounds, such as levoglucosan. The GC-MS OAM is fully automated and has been successfully deployed in the field. It uses a chemically deactivated filter for collection followed by thermal desorption and GC-MS analysis. Laboratory tests show that detection limits range from 0.2 to 3 ng for many atmospherically relevant compounds. The GC-MS OAM was deployed in the field for semi-continuous measurement of the organic markers, levoglucosan, dehydroabietic acid, and several polycyclic aromatic hydrocarbons (PAHs) during winter (January to March), 2015 and 2016. Results illustrate the significance of this monitoring technique to more fully characterize the organic components of PM and identify sources of pollution. </p><p> Keywords: air pollution, fine particulate matter, PM_2.5, secondary organic aerosol, organic markers, levoglucosan, PMF. </p>

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