This UCLA Center comprises 3 continuing research projects centered around the key role and mechanisms by which particulate pollutants induce airway inflammation. All projects focus on oxidative stress as a central mechanism by which xenobiotics mediate adjuvant effects in allergic airway inflammation through a hierarchy of cytoprotective/anti-oxidant (Tier 1), inflammatory (Tier 2) and finally, if unchecked, cytotoxic (Tier 3) responses. Cross-cutting themes in this Center are particulate pollutants and pro-oxidative chemicals, cellular and molecular targets of oxidative stress, genetics of disease susceptibility and high responder status, development of rational interventions, and use of established human and murine models. The senior investigators, Drs. Nel, Saxon, and Diaz-Sanchez are long-term AADCRC participants. Dr. Riedl, a young translational research scientist has joined and will work with Dr. Saxon as co-project leader in a human interventional project. He brings advanced clinical research skills to this Center. Project 1 (Nel) focuses on the role of the dendritic cells as key initial participants in the biological effects of particulates. This project assesses the effects of the hierarchical oxidative stress pathways in the adjuvant effects of PM on dendritic cell function so as to initiate and drive increased Th-2 like inflammation at the interface between the innate and adaptive immune system. In Project 2 (Saxon/Riedl), 3 distinct human in vivo challenge models are used in clinical studies testing the hypothesis that induction of phase II anti-oxidant enzymes (Tier 1) leads to decreased pro-oxidative effects of DEP and thereby inhibits inflammation (Tier 2) in response to DEP-driven primary and secondary allergic responses. Project 3 (Diaz-Sanchez) extends in vivo human challenge studies with ambient fine and ultrafine particles to test the hypothesis that differences in the abilities of """"""""real life"""""""" particles to generate oxidative stress, determine inflammatory outcomes. This project will also study the genetics of PM susceptibility to particulates in high vs. low DEP responders. All projects will collaborate in a discovery process using gene array and proteomics to search for oxidative stress markers that define response type & level, susceptibility and response to therapeutic intervention. An Administrative/ Subject Recruitment/Sample Core, an Ambient Particle Collection Core, and a Proteomics core provide critical resources for all the Center's projects.
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