Molecular Mechanisms of Olfactory Receptor Choice

嗅觉受体选择的分子机制

基本信息

批准号：
8085815
负责人：
RANDALL R REED
金额：
$ 32.96万
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 2013-06-30
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是由分子，细胞和组织水平的贡献产生的，以建立感觉器官。这种发育过程中最重要的组成部分之一是嗅觉受体（OR）蛋白。这个相关的GPCR耦合受体的大家庭主要负责定义可以被生物体检测到的气味范围。每个嗅觉神经元对信息编码表达单一类型或重要意义的观察结果。也就是说，可以将配体/或与单个受体类型相互作用的后果直接转化为生理信号，即细胞在大脑前部传播到嗅球。此外，根据或根据每个单元表达的轴突输入分离到嗅球中，扩展了这种关系，以使每个离散的glomeruli表示一个信息单位，该信息单位报告了报告挥发物是否存在于环境中。尽管嗅球和较高的大脑区域对这种初始信号进行了广泛的进一步处理，以产生与哺乳动物嗅觉相关的气味的复杂感知和鉴定，但在每个成熟的嗅觉神经元中的选择性表达恰恰对于该感官系统中的准确信息流至关重要。在没有这种高度调节的表达机制的情况下，嗅觉受体神经元（ORN）的反应谱以及其对嗅球的准确组织将受到严重损害。尽管具有或基因调节的重要性至关重要，但我们对本提案中与嗅觉功能的选择或调节相关的事件知之甚少，我们将定义嗅觉受体神经元所使用的关键步骤，以产生每种成熟感官神经元中单个嗅觉受体蛋白类型的选择性表达。这些实验将为建立功能性嗅觉系统的最关键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相基因表达提供了有价值的范式，这对于有助于正常健康和疾病的几种基因的适当表达至关重要。