Regulation of Odorant Receptor Gene Expression in Olfactory Sensory Neurons

描述（由申请人提供）：嗅觉辨别是通过气味受体（OR）的化学特异性及其刻板的嗅觉连接来实现的。OR是G蛋白偶联受体（GPCR）的一个大亚家族的成员。小鼠基因组中大约有1000个OR基因。每个嗅觉感觉神经元（OSN）选择只表达一个OR，并根据其OR身份将其轴突会聚到刻板的肾小球。目前尚不清楚如何在OSN中进行和维护OR选择。OR蛋白似乎在OSN特异性的OR表达和轴突靶向中起关键作用。本研究的目的是剖析OR蛋白序列中的调控基序，以确定OR介导的转录调控机制。为了进行这项研究，我们建立了一个体外系统，它允许有效的遗传操作的OR表达在其内在的细胞环境，OSN。利用这种体外系统，在目标1中，我们将检查外源OR表达是否以序列特异性方式抑制内源OR转录。在目标2中，我们将研究OR表达是否调节OSN中粘附分子的表达。通过对OR序列及其调控功能的研究，我们希望能够深入了解OR表达选择和OSN轴突导向的机制。OR调控基序的鉴定将为未来的体内研究奠定基础，并有助于临床干预措施的设计。公共卫生相关性：本研究旨在了解控制嗅觉感觉神经元在其气味受体选择和轴突靶向粘附分子表达中的身份的调节机制。

DESCRIPTION (provided by applicant): Olfactory discrimination is achieved through chemical specificity of odorant receptors (OR) and their stereotypic olfactory connections. ORs are members of a large subfamily of G-protein coupled receptors (GPCR). There are about 1000 OR genes in the mouse genome. Each olfactory sensory neuron (OSN) chooses to express only one OR and converges its axon according to its OR identity to a stereotypic glomerulus. It is not clear how the OR selection is made and maintained within the OSN. OR proteins appear to play critical roles in OSN specificity in its OR expression and axon targeting. The goal of this study is to dissect the regulatory motif within the OR protein sequence in order to define the mechanism of OR- mediated transcription regulation. To carry out this study, we established an in vitro system which allows efficient genetic manipulation of OR expression within its intrinsic cellular environment, the OSN. Utilizing this in vitro system, in Aim 1, we will examine whether exogenous OR expression suppresses endogenous OR transcription in a sequence specific manner. In Aim 2, we will examine whether OR expression regulates adhesion molecule expression in OSNs. Through dissecting OR sequence and their regulatory function, we hope to gain insights into the mechanisms of OR expression choice and OSN axon guidance. Identification of the OR regulatory motif will lay foundations for future in vivo investigations and aid in the design of clinical interventions. PUBLIC HEALTH RELEVANCE: This study aims to understand the regulatory mechanism that controls the identity of olfactory sensory neurons in their odorant receptor choice and their expression of adhesion molecules for axon targeting.