Molecular basis of olfactory perception.

嗅觉感知的分子基础。

• 批准号: 7388921
• 负责人: DAVID NIGEL JONES
• 金额: $ 28.91万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388921
• 关键词: Address; Affinity; Alcohols; Amino Acid Substitution; Animals; Anopheles gambiae; Behavior; Behavioral; Binding; Biological Process; Bite; Blood; Cessation of life; Chemicals; Classification; Communicable Diseases; Complex; Cues; Culicidae; Data; Detection; Disease; Drosophila melanogaster; Event; Female; Goals; Hair; Human; Incidence; Individual; Insecta; Lead; Ligand Binding; Ligands; Location; Malaria; Mediating; Methods; Molecular; Molecular Conformation; Molecular Target; NMR Spectroscopy; Nature; Neurons; Nuclear Magnetic Resonance; Numbers; Odorant Receptors; Odors; Organ; Parasites; Pattern; Perception; Pheromone; Plasmodium falciparum; Play; Property; Proteins; Range; 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; numb protein; 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，每年造成1-200万人死亡。疟疾是通过感染疟原虫的雌性蚊子的咬伤来传播的。该物种的雌性蚊子冈比亚几乎完全以人类为食，并使用人类汗水和皮肤中存在的气味来定位其靶标，并将人类与其他动物区分开。该提案的总体目标是了解控制蚊子寻求宿主行为的分子事件，以开发新方法以减少疟疾的传播。昆虫检测的气味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将气味分子从嗅觉（Sensilla）的表面传输到受体，并积累的证据表明，OBP可以直接介导某些ODORANT受体的活性。在雌性冈比亚蚊子中，许多OBP的表达模式与寻求宿主的行为的变化相关。因此，假设这些蛋白质可能与介导对人类气味的嗅觉反应有关。该建议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如何与人类特异性气味相互作用。该提案将使用核磁共振（NMR）光谱法来确定哪些气味与特定的OBP相互作用。随后，我们将确定这些复合物的三维结构，并将特定气味的结合亲和力与OBP和气味剂之间发生的特定相互作用的结合亲和力差异相关。我们将寻求回答问题； Agobps是否作为响应人类气味的嗅觉信号传导的特定调节剂？配体是否会在Agobps中诱导特定的构象变化，以表明在激活气味受体中的直接作用？一旦定义了特定的AgoBps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，以破坏正常的蚊蚊行为，从而减少疟疾的传播。