Molecular basis of olfactory perception.

嗅觉感知的分子基础。

• 批准号: 8012829
• 负责人: DAVID NIGEL JONES
• 金额: $ 27.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-24 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012829
• 关键词: Address; Affinity; Alcohols; Amino Acid Substitution; Animals; Anopheles gambiae; Behavior; Behavioral; Binding; Biological Process; Bite; Blood; Cessation of life; Chemicals; Communicable Diseases; Complex; Cues; Culicidae; Data; Detection; Disease; Drosophila melanogaster; Event; Feeds; Female; Goals; Hair; Health; Human; Incidence; Individual; Insecta; Lead; Ligand Binding; Ligands; Location; Malaria; Mediating; Methods; Molecular; Molecular Conformation; Molecular Target; NMR Spectroscopy; Nature; Neurons; Nuclear Magnetic Resonance; Odorant Receptors; Odors; Organ; Parasites; Pattern; Perception; Pheromone; Plasmodium falciparum; Play; Property; Proteins; Reagent; Receptor Activation; Research Personnel; Role; Series; Signal Transduction; Skin; Specificity; Structure; Surface; Sweat; Sweating; System; Testing; X-Ray Crystallography; base; design; feeding; foot; in vivo; insight; method development; odorant-binding protein; olfactory receptor; programs; protein structure; protein transport; receptor; reproductive; response; three dimensional structure; transmission process; vector transmission

DESCRIPTION (provided by applicant): Malaria is one of the world's most devastating diseases and is responsible for between 1-2 million deaths each year. Malaria is transmitted by the bite of a female mosquito infected with the malaria parasite. Female mosquitoes of the species Anopheles gambiae are feed almost exclusively on humans and use odors present in human sweat and skin to locate their targets and discriminate humans from other animals. The overall goal of this proposal is to understand the molecular events that control the host seeking behavior of the mosquito in order to develop new methods to reduce the transmission of malaria. Odor detection by an insect requires the interaction of a number of protein components. Among these are the Odorant Receptors and the Odorant Binding Proteins (OBPs). The OBPs transport the odor molecule from the surface of the olfactory hairs (sensilla) to the receptors and accumulating evidence suggests that OBPs may directly mediate the activity of some odorant receptors. In female A. gambiae mosquitoes, the expression patterns of a number of OBPs correlate with changes in the host-seeking behavior. Therefore, it is hypothesized that these proteins may be associated with mediating olfactory responses to human odors. This proposal will investigate how these OBPs interact with human-specific odors by examining the structure and ligand-binding properties of these proteins. This proposal will use Nuclear Magnetic Resonance (NMR) Spectroscopy to identify which odors interact with specific OBP. Subsequently we will determine the three-dimensional structure of these complexes, and correlate differences in binding affinities for particular odorants with specific interactions that occur between the OBP and the odorant. We will seek to answer the questions; do AgOBPs act as specific modulators of olfactory signaling in response to human odors? Do ligands induce specific conformational changes in the AgOBPs that could indicate a direct role in activation of odorant receptors? Once the nature of the interactions between specific AgOBPs and odor molecules are defined, this information will be used to guide the design of new reagents targeted at OBPs, with the aim of disrupting normal Anopheline mosquito behavior and so reducing the transmission of malaria.

描述（由申请人提供）：疟疾是世界上最具破坏性的疾病之一，每年导致 1-200 万人死亡。疟疾是通过感染疟原虫的雌性蚊子叮咬传播的。冈比亚按蚊的雌性蚊子几乎只以人类为食，它们利用人类汗液和皮肤中的气味来定位目标并将人类与其他动物区分开来。该提案的总体目标是了解控制蚊子寻找宿主行为的分子事件，以便开发减少疟疾传播的新方法。昆虫的气味检测需要许多蛋白质成分的相互作用。其中包括气味受体和气味结合蛋白（OBP）。 OBP 将气味分子从嗅毛（感器）表面转运至受体，越来越多的证据表明 OBP 可能直接介导某些气味受体的活性。在雌性冈比亚蚊子中，许多 OBP 的表达模式与寻找宿主行为的变化相关。因此，推测这些蛋白质可能与介导对人类气味的嗅觉反应有关。该提案将通过检查这些蛋白质的结构和配体结合特性来研究这些 OBP 如何与人类特有的气味相互作用。该提案将使用核磁共振 (NMR) 光谱来识别哪些气味与特定的 OBP 相互作用。随后，我们将确定这些复合物的三维结构，并将特定气味剂的结合亲和力差异与 OBP 和气味剂之间发生的特定相互作用相关联。我们将寻求回答这些问题； AgOBP 是否充当响应人类气味的嗅觉信号的特定调节剂？配体是否会诱导 AgOBP 发生特定的构象变化，从而表明其在气味受体激活中的直接作用？一旦确定了特定 AgOBP 和气味分子之间相互作用的性质，该信息将用于指导针对 OBP 的新试剂的设计，目的是破坏按蚊的正常行为，从而减少疟疾的传播。