Nitric oxide (NO) mediates cell signaling via cGMP- and non-cGMP-dependent reactions and yields secondary oxides of nitrogen (NOx) that expand the range of molecular targets of NO via oxidation, nitrosation and nitration reactions. The reactions of NO and its products with unsaturated fatty acids transduces NO signaling via the formation of electrophilic nitro-fatty acids, generically termed N02-FA. The research objectives set for the upcoming renewal of this R37/Merit award will continue to probe the concept that inflammatory-derived electrophilic fatty acids are redox signaling mediators that work in tandem with their highly conserved molecular targets (e.g., transcriptional regulatory proteins) to regulate adaptive cell signaling events. These reactions permit organisms to link gene expression with their metabolic, environmental and inflammatory status. Importantly, there still remains a lack of knowledge regarding the structural properties and biochemical reactivities of N02-FA that account for their induction of adaptive cell signaling responses. We will utilize HPLC-MS/MS to characterize the patterns and mechanisms of EFOX production during conditions relevant to obesity-induced diabetes. After learning more about the structural characteristics, concentrations, metabolism and molecular targets of specific EFOXs, we will evaluate the therapeutic potential of synthetic homologs of key EFOXs by administering these species in the setting of a model of obesity-induced diabetes, high fat diet-fed C57/BI6 mice. It is hypothesized that the electrophilic derivatives of unsaturated fatty acids formed by the oxidative inflammatory milieu mediate adaptive cell signaling responses. This hypothesis will be tested by pursuing three Specific Aims: 1. Structurally characterize and quantitate the predominant electrophilic fatty acid species present in the inflammatory milieu of obesity, using cell, rodent and clinically-derived specimens. 2. Define the contribution of mitochondrial redox reactions in the formation of electrophilic derivatives of unsaturated fatty acids. 3. Examine the anti-inflammatory actions of electrophilic fatty acids in cell and animal models of obesityinduced diabetes.
The research plan capitalizes on the discovery that nitro- and keto-fatty acid derivatives are potent and broadly-acting anti-inflammatory mediators. We will a) identify new inflammatory-derived fatty acid electrophiles, and b) better understand the salutary cell signaling and physiological actions of these endogenously-produced electrophilic fatty acids and c) begin to develop these species as a new drug class.
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