Compromised Resolution of Inflammation following Nanoparticle Exposure in Metabolic Syndrome

代谢综合征中纳米颗粒暴露后炎症的消退效果受损

• 批准号: 10441741
• 负责人: Jonathan Henry Shannahan
• 金额: $ 33.77万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441741
• 关键词: Address; Carbon Black; Chronic Disease; Data; Deposition; Development; Disease; Disease Progression; Environmental Exposure; Evaluation; Exhibits; Exposure to; Glycerol; Goals; Health; Health protection; Histologic; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Inhalation Exposure; Kinetics; Knowledge; Laboratories; Lipids; Lipolysis; Lung; Lung Lavage Fluid; Mediating; Mediator of activation protein; Metabolic syndrome; Metabolism; Modification; Molecular; Mus; Omega-3 Fatty Acids; Particulate; Particulate Matter; Pathologic; Pathway interactions; Pattern; Pharmacology; Population; Predisposition; Prevention strategy; Process; Production; Progressive Disease; Proteomics; Public Health; Pulmonary Surfactant-Associated Protein D; Research; Resolution; Risk Assessment; Role; Safety; Signal Transduction; Silver; Sphingomyelins; Surface; Testing; Therapeutic Intervention; Toxic effect; base; cohort; disorder prevention; environmental particulate; fatty acid metabolism; in vitro Model; in vivo; inflammatory modulation; inhibitor; innovation; lipid metabolism; lipidomics; mass spectrometric imaging; metal oxide; mouse model; nanoparticle; nanoparticle exposure; nanosized; novel; novel therapeutic intervention; receptor; receptor expression; response; targeted treatment; therapy development; treatment strategy

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.

项目摘要/摘要