Molecular Biology of the Odorant Receptors

气味受体的分子生物学

基本信息

批准号：
7849880
负责人：
Leslie B Vosshall
金额：
$ 15.95万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7849880
关键词：
Address Adopted Afferent Neurons Anopheles gambiae Behavior Behavioral Binding Biochemical Biological Biological Assay Caenorhabditis elegans Calmodulin Cells Chemical Agents Cilia Communicable Diseases Complex Consensus Couples Cues Culicidae Cyclic Nucleotides Cytoplasm Dendrites Dengue Disease Vectors Drosophila genus Drosophila melanogaster Encephalitis Family Family member Future G-Protein-Coupled Receptors Gated Ion Channel Goals Heterotrimeric GTP-Binding Proteins Human In Vitro Individual Inositol Phosphates Insect Vectors Insecta Knowledge Maintenance Malaria Mediating Membrane Proteins Methods Modification Molecular Molecular Biology Molecular Chaperones Molecular Structure Mutagenesis Nematoda Odorant Receptors Odors Pathway interactions Phosphorylation Play Post-Translational Protein Processing Production Proteins Research Design Research Personnel Role Sensory Sequence Homology Signal Transduction Site Structure System Techniques Tertiary Protein Structure Testing Translating Transmembrane Domain Ursidae Family Vertebrates Visual West Nile virus Work Yellow Fever cellular imaging design disease transmission human disease in vivo insect disease member mutant novel programs receptor function receptor structure function trafficking

项目摘要

Insect vectors of human disease infect hundreds of millions of individuals annually with deadly infectious diseases, including Malaria, Dengue and Yellow Fever, and West Nile Encephalitis. Insects are attracted to human hosts by specific sensory cues, with olfactory cues playing a dominant role. The Broad," Long-Term Objectives of this proposal are to understand the mechanisms by which the olfactory system allows insects to hone in on human hosts. Such knowledge could be translated to a new class of chemical agents that act on the insect olfactory system to interrupt vector insect host-seeking behavior. Responsive to PA-05-154, the overall goal of this specific project is to increase understanding of the molecular structure and function of the odorant receptors (ORs) that mediate odor recognition in insects. In preliminary studies, we have documented a unique chaperoning co-receptor function for OR83b. OR83b is co-expressed and forms OR/ OR83b heterodimers with conventional ORs in most olfactory sensory neurons in vivo and is necessary for the targeting and maintenance of ORs in ciliated dendrites where odor transduction occurs. These preliminary studies have led to the hypothesis that the OR/OR83b complex is essential for insect olfactory function. To test this hypothesis, three Specific Aims are proposed: 1) Identify protein domains that mediate OR83b targeting to olfactory cilia 2) Define protein domains that mediate the formation of heteromeric OR/OR83b complexes 3) Characterize post-translational modifications that modulate the OR/OR83b complex The Research Design involves targeted mutagenesis of OR83b to uncover motifs necessary for trafficking, OR/OR83b heteromerization, and post-translational modifications. The Methods used are phenotypic analysis of Drosophila OR function in vivo and in vitro employing electrophysiological, imaging, cell biological, biochemical, and behavioral techniques. A molecular understanding of insect OR function may aid in the design of novel chemical agents that selectively disrupt insect ORs and thus interrupt host- seeking behaviors of insect disease vectors such as mosquitoes. The Health-Relatedness of this proposal is that such chemical agents may act to reduce infectious disease transmission by vector insects in the future.

人类疾病的昆虫媒介每年使数亿人感染致命的传染病疾病，包括疟疾、登革热和黄热病以及西尼罗河脑炎。昆虫被吸引人类宿主通过特定的感官线索，其中嗅觉线索起主导作用。广泛的、长期的该提案的目的是了解昆虫的嗅觉系统的机制专注于人类宿主。这些知识可以转化为一类新的化学制剂，其作用作用于昆虫嗅觉系统以中断媒介昆虫寻找宿主的行为。响应 PA-05-154，这个特定项目的总体目标是增加对分子结构和功能的了解介导昆虫气味识别的气味受体（OR）。在初步研究中，我们有记录了 OR83b 独特的陪伴共受体功能。 OR83b 共表达并形成 OR/ OR83b 异二聚体与体内大多数嗅觉感觉神经元中的常规 OR 是必需的发生气味转导的纤毛树突中 OR 的靶向和维持。这些初步研究得出这样的假设：OR/OR83b 复合物对于昆虫嗅觉至关重要功能。为了检验这一假设，提出了三个具体目标： 1) 鉴定介导 OR83b 靶向嗅觉纤毛的蛋白质结构域 2) 定义介导异聚OR/OR83b复合物形成的蛋白质结构域 3) 表征调节 OR/OR83b 复合物的翻译后修饰研究设计涉及 OR83b 的定向诱变，以发现贩运所需的基序， OR/OR83b 异聚化和翻译后修饰。使用的方法是表型的利用电生理学、成像、细胞分析果蝇体内和体外 OR 功能生物学、生化和行为技术。对昆虫或功能的分子理解可能帮助设计新型化学制剂，选择性地破坏昆虫 OR，从而中断宿主寻找昆虫疾病媒介（例如蚊子）的行为。该提案的健康相关性是此类化学制剂将来可能会起到减少媒介昆虫传播传染病的作用。