Molecular Mechanisms of Olfactory Receptor Choice

嗅觉受体选择的分子机制

基本信息

批准号：
7860335
负责人：
RANDALL R REED
金额：
$ 34.05万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The remarkable sensitivity and specificity of mammalian olfaction arises from the contributions at the molecular, cellular and tissue levels to establish a sensory organ. One of the most important components in this developmental process is the olfactory receptor (OR) protein. This large family of related GPCR coupled receptors is primarily responsible for defining the range of odorants that can be detected by an organism. The observation that each olfactory neuron expresses a single type of OR has important implications for information coding. Namely, the consequences of a ligand/OR interaction with a single receptor type can be directly translated into the physiological signal that the cell propagates to the olfactory bulb at the front of the brain. Additionally, the segregation of the axonal inputs into the olfactory bulb, organized according to the OR that each cell expresses, extends this relationship such that each discrete glomeruli represents an information unit reporting whether volatiles are present in the environment. Although extensive further processing of this initial signal by the olfactory bulb and higher brain areas is required to generate the complex perception and identification of odors associated with mammalian olfaction, the selective expression of exactly one OR in each mature olfactory neuron is critical for accurate information flow in this sensory system. In the absence of this highly regulated expression mechanism, the response profile of olfactory receptor neurons (ORNs) and the accurate organization of their projections to the olfactory bulb would be severely compromised. In spite of the critical importance of OR gene regulation, we know surprisingly little about the events associated with OR choice and regulation in olfactory function In this proposal, we will define the key steps utilized by olfactory receptor neurons to generate the selective expression of a single olfactory receptor protein type in each mature sensory neuron. These experiments will afford new insights into one of the most critical events in the establishment of a functional olfactory system and elucidate the role of specific regulatory proteins in this process. In addition, the regulation of the mammalian olfactory receptors provides a valuable paradigm for monoallelic gene expression that is critical for the proper expression of several genes that contribute to normal health and disease.

描述（由申请人提供）：哺乳动物嗅觉的显着敏感性和特异性源于在分子、细胞和组织水平上对建立感觉器官的贡献。这个发育过程中最重要的组成部分之一是嗅觉受体（OR）蛋白。这个相关 GPCR 偶联受体的大家族主要负责定义生物体可以检测到的气味范围。每个嗅觉神经元表达单一类型 OR 的观察结果对于信息编码具有重要意义。也就是说，配体/OR与单一受体类型相互作用的结果可以直接转化为细胞传播到大脑前部嗅球的生理信号。此外，根据每个细胞表达的 OR 组织的轴突输入到嗅球的分离扩展了这种关系，使得每个离散的肾小球代表一个报告环境中是否存在挥发物的信息单元。尽管需要嗅球和高级大脑区域对这一初始信号进行广泛的进一步处理，以产生与哺乳动物嗅觉相关的复杂气味的感知和识别，但每个成熟嗅觉神经元中恰好一个 OR 的选择性表达对于准确的信息流至关重要在这个感觉系统中。如果缺乏这种高度调控的表达机制，嗅觉受体神经元（ORN）的反应特征及其向嗅球投射的准确组织将受到严重损害。尽管 OR 基因调控至关重要，但令人惊讶的是，我们对与 OR 选择和嗅觉功能调控相关的事件知之甚少。在本提案中，我们将定义嗅觉受体神经元用于生成单个嗅觉选择性表达的关键步骤。每个成熟感觉神经元中的嗅觉受体蛋白类型。这些实验将为建立功能性嗅觉系统中最关键的事件之一提供新的见解，并阐明特定调节蛋白在此过程中的作用。此外，哺乳动物嗅觉受体的调节为单等位基因表达提供了有价值的范例，这对于有助于正常健康和疾病的几个基因的正确表达至关重要。