Perireceptor Contributions to Chemical Communication

描述(由申请人提供)：感官信息的感知在社会和性行为中起着关键作用。嗅觉刺激已被证明可以引发重要的反应，如雄性间攻击、性唤醒、青春期加速和发情同步。在包括人类在内的许多哺乳动物中，这些交流刺激已被鉴定为疏水的、易挥发的小分子。这些通讯化学物质在生物体液中浓度很高，通过与鼻神经上皮细胞的特殊受体结合来激活特定的感觉神经元。虽然在阐明这些受体的性质和导致其传播到大脑的转导途径方面已经取得了相当大的进展，但我们对亲水性鼻腔粘液中这些疏水分子的管理的关键过程知之甚少。Lipocalin的一种特殊类型，主要尿蛋白(MUPs)4和5(鼻腔MUPs)，存在于粘液中，体外研究表明，它可以选择性地结合一些小的疏水气味和信息素。然而，由于缺乏分子遗传学工具，鼻腔MUPs和其他鼻腔Lipocalin的体内功能仍未得到解决。关于它们的潜在功能有几个假说，包括：1.MUP作为配体特异性的转运体将气味和/或信息素输送到受体部位；2.MUP在转导后作为清道夫从受体上清除气味；3.MUP作为缓冲器防止受体饱和；以及4.MUP作为传导器激活受体。这一提议的总体假设是，鼻腔MUP用于选择性地结合具有生物学意义的疏水分子，并且对气味检测和随后的行为至关重要。这项建议的主要目标是应用综合的遗传、生理和行为方法来阐明鼻部MUP在哺乳动物化学交流中的生理作用以及这些化合物影响生物相关社会行为的机制。这种研究感受器周围事件的方法可能会打开化学感官研究的新途径，并扩大我们对嗅神经元以外的正常和异常感觉功能的理解。

DESCRIPTION (provided by applicant): The perception of sensory information plays a critical role in social and sexual behavior. Olfactory stimuli have been shown to elicit important responses such as intermale aggression, sexual arousal, puberty acceleration, and estrus synchronization. In many mammals, including humans, these communication stimuli have been identified as small hydrophobic, volatile molecules. These communication chemicals are present at high concentrations in biological fluids and activate specific sensory neurons by binding to specialized receptors of nasal neuroepithelia. Although there have been considerable advances in elucidating the nature of these receptors and the transduction pathway that leads to the propagation to the brain, we know very little about the critical process for managing these hydrophobic molecules in the hydrophilic nasal mucus. A specific class of lipocalins, Major Urinary Proteins (MUPs) 4 and 5 (nasal MUPs), are present in the mucus and have been shown to selectively bind a number of small hydrophobic odorants and pheromones in vitro. However, the in vivo function of the nasal MUPs as well as the other nasal lipocalins, remains unresolved largely due to the absence of molecular genetic tools. Several hypotheses have been postulated regarding their potential function including: 1. MUPs function as ligand-specific transporters delivering odorant and/or pheromones to receptor sites, 2. MUPs function as scavengers removing odorants from the receptor after transduction, 3. MUPs act as buffers preventing saturation of the receptors, and 4. MUPs act as transducers that activate the receptor. The overall hypothesis of this proposal is that nasal MUPs serve to selectively bind biologically meaningful hydrophobic molecules and are critical for odorant detection and subsequent behavior. The primary goal of this proposal is to apply integrated genetic, physiological and behavioral methods to elucidate the physiological role for nasal MUPs in mammalian chemical communication and the mechanisms whereby these compounds influence biologically relevant social behaviors. This approach to studying perireceptor events may open new avenues of research in the chemical senses and expand our understanding of normal and abnormal sensory function beyond the olfactory neuron.