This UCLA Center proposal comprises four related research projects centered about the theme of the enhancement of airway, allergic inflammation by xenobiotic compounds generated from fossil fuel combustion. All projects address key issues regarding the pathways by investigators are original participants in this AAIDCRC. The fourth project brings on a new young investigator as Project Leader. The Projects examine clinical, cellular and molecular aspects of epithelial cells, macrophages, mast cells, basophils and lymphocytes all of which involved in allergic inflammation. In Project 1 (SAXON), the human in vivo challenge models developed in this enter will be used to test therapeutic approaches to inhibiting allergic in response to DEP and allergen. This will include the use of models of both primary sensitization and secondary boosting of allergic inflammation. """"""""Proof of Principle:"""""""" approaches will be directed at i) anti-oxidants, ii) interrupting cytokine signaling (sIL-4R) and iii) deviation of the local immune response via CpG administration. In Project 2, (NEL) the role of oxidative stress in the generation of biological effects by DEP chemical will be studied by focusing on pro-inflammatory and anti-oxidant defense pathways. This will include the use of tissue culture macrophages and epithelial cells in vitro, as well as in vivo exposure of animals and humans to determine how a sensitive oxidant stress enzyme, heme oxygenase 1 (HO-1), protects against the pro-oxidative and pro-inflammatory effects of DEP. These studies will determine how modification of the HO-1 gene response pathway may predispose animals and humans to exaggerated allergic inflammatory responses. In Project 3 (HERSCHMAN), the mechanisms and consequences of DEP inhibition of prostaglandin products will be examined in cells, and in murine model of allergic airway inflammation and in human airway (PG) production will be examined genetically and pharmacologically in cells and in the animal challenge model. The basis for arachidonic acid sequestration in COX-1 vs. COX-2 PG synthesis will be elucidated, with a goal of utilizing this information to modulate immediate vs. delayed mast cell PGD2 production during inflammatory response. Difference in signaling pathways modulating COX-2 induction in mast cells vs. macrophages will be clarified, to provide cell-type specific approaches to pharmacologic modulation of PG production. Project 4 (Diaz-Sanchez) will determine the role of defined metabolic pathways for DEP xenobiotics and their relevant genes/gene products in mediating the allergic inflammatory responses to inhal4ed DEP in murine models of asthma. Advantage will also be taken of known functional human polymorphisms important oxidative stress pathways (GST and NQO1) to test whether they alter the responses to in vivo nasal DEP challenge. These studies identifying the pathways by which DEP, as a model xenobiotic, induce their effects on allergic inflammation will provide information in the other Center projects. The studies in this Center focus on xenobiotic modulation of mucosal allergic inflammation, using diesel exhaust particles as a relevant prototype. The project leaders comprise three senior investigators and one young investigator, each of whom has independent functioning but for whom the Center grant is the sole source of support for these studies on DEP. The projects are supported by a DEP collection and fractionation core, a mouse core, and a administrative, patient and sample coordination core.
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