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 in hydrophobic tissue compartments (e.g., lipoproteins, membranes) also transduce .NO signaling. This research project focuses on identifying the specific chemical reactivities, biodistribution and signaling actions of nitrated fatty acids (generically termed "NO2-FA"). Current data support that NO2-FA represent inflammatory byproducts that serve as adaptive mediators of inflammation. Importantly, there remains a lack of knowledge regarding the structural properties and biochemical reactivities of NO2-FA that account for their induction of adaptive cell signaling responses. A central hypothesis provides focus to the proposed research plan: specifically, that nitro-fatty acids mediate adaptive cell signaling reactions that regulate metabolism and inflammation. This hypothesis will be tested by pursuing the following Specific Aims: #1. Synthesize and characterize selected nitro-fatty acid regioisomers;#2. Explore the mechanisms of PPAR receptor binding and activation by nitro-fatty acids;#3. Define the actions of nitro-fatty acids in an animal model of metabolic disease. Accomplishment of this research plan will fill the void in our current understanding of the chromatographic behavior, structural characteristics, reactivity and consequent in vitro and in vivo signaling actions of NO2-FA derivatives, thus better guiding the design of more efficacious pharmacologic modulators of metabolic and inflammatory signaling.
This proposed research plan investigates the chemical biology and pharmacology of a new class of signaling mediators derived by the nitration of fatty acids. Clinically-significant signaling actions of these species will be explored by defining the basis for their unique and potent activation of the nuclear lipid receptor peroxisome proliferator activating receptor-3 (PPAR3) that is displayed by at least one facet of this class of signaling mediators. Overall, successful accomplishment of this innovative proposed study holds exciting new promise for the treatment of diseases associated with aging, such as arteriosclerosis, hypertension and diabetes.
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