Molecular Mechanisms of Olfactory Receptor Choice

描述（由申请人提供）：哺乳动物嗅觉的灵敏和辨别能力来自于新的遗传调控机制、细胞特化以及嗅觉系统的整体解剖和结构的结合。遗传控制的一个关键方面是单个嗅觉受体（OR）基因在每个感觉神经元中的一个等位基因的选择性表达。过去在该领域的研究已经证明了这种一受体一神经元原理，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测这些过程的复杂性和工作量，对这一调控过程的分子理解受到了阻碍。包括我们在内的几位研究人员在转基因小鼠中进行的实验表明，受体编码序列在决定转录状态方面起着额外的关键作用

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.