Molecular Mechanisms Underlying Odorant Recognition

描述（由申请人提供）：人类通过嗅觉和味觉检测化学物质的能力对于维持我们日常生活的质量至关重要，从享受美食和鲜花到发现火灾和变质的食物。我们的长期目标是了解化学物质如何在外围感觉器官中被检测到，大脑如何处理信息以识别化学物质，以及大脑如何指导适当的行为反应。这些过程对动物的生存和繁殖至关重要。如果没有功能性的嗅觉和味觉系统，动物在探测和评估食物、寻找捕食者、猎物、交配伴侣和环境中的有害化学物质方面就会有困难。尽管哺乳动物嗅觉受体（ORs）早在15年前就被发现，但尚未全面了解不同气味分子如何在分子水平上与ORs相互作用。为了解决这个问题，对ORs和OR配体特异性的生物合成有更全面的了解是很重要的。这方面的进展一直很缓慢，主要是由于缺乏一种有效的系统来识别激活ORs的配体。在目前的资助期内，我们在嗅觉和味觉系统方面都取得了进展。在嗅觉系统中，我们发现了RTP1和RTP2这两种辅助分子可以增强ORs的细胞表面表达，使我们能够在异源细胞中功能性地表达ORs。利用这种方法，我们确定了一组哺乳动物ORs的活性配体。在味觉系统中，我们确定了PKD1L3和PKD2L1作为候选的酸味受体。公共卫生相关性：世界上没有一个科学家或调香师能够观察到一种新的分子结构并预测它的气味，很大程度上是因为缺乏对特定气味激活哪些气味受体的知识。这里提出的研究目标是加深我们对气味受体如何检测气味的理解。这些研究可能有助于理解嗅觉功能障碍，并开发新的方法来提高我们的日常生活质量——从享受美食和鲜花到探测火灾和变质的食物。

DESCRIPTION (provided by applicant): Human's ability to detect chemicals though our sense of smell and taste is essential to maintain the quality of our daily life, from enjoying meals and flowers to detecting fire and spoiled food. Our long-term objective is to understand how chemicals are detected in the peripheral sense organs, how the information is processed in the brain to recognize chemicals, and how the brain directs appropriate behavioral responses. These processes are critical for animals to survive and reproduce. Without functional olfactory and gustatory systems, animals have difficulties in detecting and evaluating food, finding predators, prey, mating partners, and noxious chemicals in the environment. Although mammalian odorant receptors (ORs) were identified over 15 years ago, comprehensive understanding of how different odorant molecules interact with ORs at a molecular level has not been achieved. To address this, it is important to have a more complete understanding of the biosynthesis of ORs and OR ligand specificities. Progress on this front has been slow, largely due to the lack of an efficient system for identifying ligands that activate the ORs. In the current grant period, we have made progress in both the olfactory and gustatory systems. In the olfactory system, we identified RTP1 and RTP2, accessory molecules that enhance the cell-surface expression of ORs, enabling us to functionally express ORs in heterologous cells. Using this approach, we identified a set of active ligands for mammalian ORs. In the gustatory system, we identified PKD1L3 and PKD2L1 as candidate sour taste receptors. The Public Health Relevance: There is not a scientist or perfumer in the world who can view a novel molecular structure and predict how it will smell, largely due to a lack of knowledge about which odorant receptors are activated by a given odor. The goals of the studies proposed here are to deepen our understanding of how odorants are detected by odorant receptors. These studies may help understand olfactory dysfunction and develop new ways to improve the quality of our daily life - from enjoying meals and flowers to detecting fire and spoiled food.