The specificity of odor recognition by Anopheles gambiae odorant binding proteins (OBPs) and odorant receptors (ORs) will be investigated and correlated with quantifiable physiological and behavioral responses. For olfactory proteins involved in the detection of human hosts, OBP-OR pairs residing in common antennal olfactory sensilla and recognizing common host-related ligands will be identified using high-throughput screening assays employing purified recombinant OBPs, reconstituted insect cell-based OR expression platforms and libraries of synthetic and natural compounds. OBP crystal-based structure determination and modeling of ligand fitting into OBP and OR ligand-binding pockets will also be carried out in order to design ligand mimetics with improved binding and functional properties. The effectiveness of newly identified ligands will be established by in vivo electrophysiological and behavioral assays on female mosquitoes. Finally, lead compounds acting as disruptors of normal olfactory and host seeking mosquito behavior but lacking mammalian cell toxicity will be tested in model sites in Africa where A. gambiae (and malaria) is endemic to determine efficacy characteristics under conditions that simulate the sites of possible application of newly developed products. This approach to dissecting mosquito vector olfactory function should yield results that will enhance our understanding of the mechanisms that control odor recognition in mosquitoes. The identification of multiple disruptors of host seeking behavior of female mosquitoes will provide multiple new and effective tools to be employed in the effort to reduce the incidence of contact between the human host and the insect vector carrying the malaria parasite. Last but not least, the outcome of the proposed studies should serve as a paradigm for analogous efforts aimed at a reduction in disease transmission by other disease-carrying insect vectors.
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