Molecular Mechanisms of Olfactory Receptor Choice

嗅觉受体选择的分子机制

• 批准号: 8801138
• 负责人: RANDALL R REED
• 金额: $ 34.43万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8801138
• 关键词: 5' Untranslated Regions; Afferent Neurons; Alleles; Anatomy; Architecture; Area; Base Sequence; Biology; Cell Culture System; Cell Culture Techniques; Cell Line; Cells; Chromatin; Code; Complex; Controlled Study; DNA; DNA Sequence; Discrimination; Disease; Doxycycline; Elements; Ensure; Epigenetic Process; Exons; Feedback; G Protein-Coupled Receptor Genes; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetically Modified Animals; Genome; Genomics; Grant; Health; Human; Knock-in Mouse; Knowledge; Laboratories; Ligands; Location; Messenger RNA; Methods; Modeling; Molecular; Molecular Genetics; Mus; Neurons; Nucleic acid sequencing; Odorant Receptors; Olfactory Receptor Neurons; Open Reading Frames; Pathway interactions; Play; Polyadenylation; Process; Promoter Regions; Proteins; Receptor Gene; Regulation; Regulatory Element; Regulatory Pathway; Reporter; Research; Research Personnel; Role; Site; Smell Perception; Specificity; System; Testing; Tissues; Trans-Activators; Transgenic Mice; Transgenic Organisms; biological systems; functional genomics; genetic analysis; in vivo; in vivo Model; information processing; insight; molecular array; neuron development; novel; olfactory bulb; olfactory marker protein; olfactory receptor; programs; promoter; receptor; receptor expression; research study; response; selective expression

DESCRIPTION (provided by applicant): The exquisite sensitivity and discrimination capabilities of mammalian olfaction arise from a combination of novel genetic regulatory mechanisms, cellular specializations, and the overall anatomy and architecture of the olfactory system. One of the key aspects of genetic control is the selective expression of one allele of a single olfactory receptor (OR) gene in each sensory neuron. Past research in this area has demonstrated this one-receptor one-neuron principle and revealed an important role for the olfactory receptor protein for feedback that establishes and maintains this relationship. A molecular understanding of processes underlying this regulation has been hampered by the complexity and effort required to examine these process in genetically modified animals. Experiments in transgenic mice by several investigators, including our own, have suggested an additional critical role for the receptor coding sequence in determining the transcription state of the receptor. In this grant we will use molecular and genetic approaches to elucidate mechanisms responsible for the remarkable regulation of OR expression. We will test the hypothesis that nucleic acid sequences within the protein coding regions of ORs control functional expression at the genomic, transcriptional or translational level and that this activityis important for proper OR expression. In specific aim 1, we utilize a cell culture model to investigate and understand mechanistically one aspect of OR expression. In parallel, we propose to determine the sequences within the OR coding sequence that are responsible for this unusual regulatory process. In specific aim 2, we will utilize genetically modified mice to examine the consequences of altering this regulation in vivo. Together, these experiments may reveal new mechanisms of gene regulation. The proposed research will incorporate novel expression systems and a broad array of molecular methods to systematically study a regulatory process that is likely to be shared by other biological systems Elucidating these mechanisms may provide additional insight in genes that play critical roles in human health and disease.

描述（由申请人提供）：哺乳动物嗅觉的敏锐敏感性和辨别能力源自新颖的基因调节机制、细胞特化以及嗅觉系统的整体解剖学和结构的组合。遗传控制的关键方面之一是单个嗅觉受体（OR）基因的一个等位基因在每个感觉神经元中的选择性表达。该领域过去的研究已经证明了这种单受体单神经元原理，并揭示了嗅觉受体蛋白在建立和维持这种关系的反馈中的重要作用。由于在转基因动物中检查这些过程所需的复杂性和工作量，阻碍了对这一调控过程的分子理解。包括我们自己在内的几位研究人员在转基因小鼠中进行的实验表明，受体编码序列在确定基因转录状态方面发挥着额外的关键作用。 受体。在这笔资助中，我们将使用分子和遗传学方法来阐明 OR 表达显着调节的机制。我们将测试以下假设：OR 的蛋白质编码区内的核酸序列在基因组、转录或翻译水平上控制功能表达，并且这种活性对于正确的 OR 表达很重要。在具体目标 1 中，我们利用细胞培养模型来研究和理解 OR 表达的一个方面。同时，我们建议确定 OR 编码序列中负责这种不寻常调节过程的序列。在具体目标 2 中，我们将利用转基因小鼠来检查改变体内这种调节的后果。总之，这些实验可能揭示基因调控的新机制。 拟议的研究将结合新颖的表达系统和广泛的分子方法来系统地研究可能由其他生物系统共享的调节过程。阐明这些机制可能会为在人类健康和疾病中发挥关键作用的基因提供更多见解。