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Principal Investigator: Jonathan Henry Shannahan
Organization: PURDUE UNIVERSITY
Fiscal Year: 2024
Award: $337,723
Funding agency: National Institute of Environmental Health Sciences
Project Summary / Abstract
Individuals with metabolic syndrome (MetS) compose a significant and growing proportion of our U.S. and global
population (> 25%). It has been established that the presence of chronic diseases, such as MetS, enhances and
prolongs environmental exposure-induced inflammation. Individuals with MetS have demonstrated enhanced
inflammation due to ambient particulate matter exposures of which a significant proportion is nano-sized. The
mechanisms associated with this enhanced susceptibility represent a significant gap in our knowledge. Mounting
data from the Shannahan laboratory suggests that dysregulation of inflammatory resolution contributes to the
exacerbated toxicity and disease progression observed in MetS. Specifically, nanoparticle inhalation exposures
induce a pulmonary inflammatory response that is exacerbated and extended due to MetS. This inflammatory
response corresponds with suppression of specialized pro-resolving mediators that facilitate inflammatory
resolution. Our data suggests following inhalation, nanoparticles gain unique biocoronas on their surface that
enhance the pro-inflammatory response while inhibiting resolution signaling. Further, our preliminary data
demonstrates MetS disrupts ω-3 fatty acid metabolism impairing resolution. This proposal examines the
hypothesis that dysregulation of inflammatory resolution following nanoparticle exposure mediates the
susceptibility observed in MetS by exacerbating inflammatory responses and facilitating development and
progression of chronic disease. The hypothesis will be tested through the completion of three main goals: 1)
Delineation of pulmonary nanoparticle-biocorona alterations throughout metabolic syndrome development and
the inflammation signaling consequences; 2) Determination of inflammatory resolution and specialized pro-
resolving mediator kinetics following nanoparticle exposure in MetS and healthy mouse models; 3) Elucidation
of differential ω-3 fatty acid metabolism in MetS following nanoparticle exposure. These mechanisms represent
potential key regulators that are dysregulated in MetS, facilitating exacerbated responses and also are potential
targets of therapeutic interventions. Typically, research and treatment strategies addressing exposure-induced
inflammation focus on suppression of pro-inflammatory pathways rather than elucidation and effective
stimulation of resolution processes. Completion of the project will generate new knowledge required to
understand distinct mechanisms of toxicity in prevalent and sensitive subpopulations such as MetS. Elucidation
of these mechanisms will allow for new disease prevention and treatment strategies while also broadening public
health protections to environmental exposures.
Terms: <1,2,3-Propanetriol><1,2,3-Trihydroxypropane><Address><Ag element><Alveolar Lavage Fluids><Bronchial Lavage Fluid><Carbon Black><Cell Communication and Signaling><Cell Signaling><Chronic Disease><Chronic Illness><Data><Development><Disease><Disease Progression><Disorder><Environmental Exposure><Evaluation><Exhibits><Exposure to><Fatty Acid Metabolism Pathway><Glycerin><Glycerol><Goals><Health><Health protection><Histologic><Histologically><Impairment><In Vitro><Individual><Inflammation><Inflammatory><Inflammatory Response><Inhalation><Inhalation Exposure><Inhaling><Intermediary Metabolism><Intracellular Communication and Signaling><Kinetics><Knowledge><Laboratories><Lipids><Lipolysis><Lung><Lung Lavage Fluid><Lung Protein D><Lung Respiratory System><Mediating><Mediator><Metabolic Processes><Metabolic syndrome><Metabolism><Mice><Mice Mammals><Modification><Molecular><Murine><Mus><Omega-3 Fatty Acids><Omega-3 PUFA><Omega-3 Polyunsaturated Fatty Acid><Omega3><Particulate><Particulate Matter><Pathologic><Pathway interactions><Pattern><Population><Predisposition><Preventative strategy><Prevention strategy><Preventive strategy><Process><Production><Progressive Disease><Proteomics><Public Health><Pulmonary Surfactant Protein D><Pulmonary Surfactant-Associated Protein D><Receptor Protein><Research><Resolution><Risk Assessment><Role><SP-D><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Silver><Sphingomyelins><Surface><Surfactant Protein D><Surfactant-Associated Glycoprotein D><Susceptibility><Testing><Therapeutic Intervention><Toxic effect><Toxicities><biological signal transduction><chronic disorder><cohort><develop therapy><developmental><disease prevention><disorder prevention><environmental particulate><fat metabolism><fatty acid metabolism><imaging mass spectrometry><in vitro Model><in vivo><inflammatory modulation><inhibitor><innovate><innovation><innovative><intervention development><intervention therapy><lipid metabolism><lipidomics><mass spectrometric imaging><metal oxide><mouse model><murine model><n-3 Fatty Acids><nano particle><nano sized><nano-sized particle><nanoparticle><nanoparticle exposure><nanosized><nanosized particle><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><omega-3><pathway><pharmacologic><pulmonary><receptor><receptor expression><resolutions><response><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapy development><treatment development><treatment strategy><ω-3 fatty acids>