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。嗅觉刺激已被证明能引起重要的反应，如雄性间的攻击、性唤起、青春期加速和发情同步。在许多哺乳动物，包括人类，这些通信刺激已被确定为小的疏水性，挥发性分子。这些通讯化学物质以高浓度存在于生物液体中，并通过与鼻神经上皮细胞的专门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传播到大脑的转导途径方面取得了相当大的进展，但我们对管理亲水性鼻粘液中这些疏水分子的关键过程知之甚少。一类特殊的脂质运载蛋白，主要尿蛋白（MUP）4和5（鼻MUP），存在于粘液中，并已显示在体外选择性结合许多小的疏水性气味剂和信息素。然而，鼻MUP以及其他鼻脂质运载蛋白的体内功能在很大程度上由于缺乏分子遗传工具而仍未得到解决。关于它们的潜在功能已经提出了几个假设，包括：1。MUPs作为配体特异性转运蛋白，将气味和/或信息素递送到受体位点，2。MUP作为清除剂在转导后从受体中去除气味，3。MUP充当缓冲剂，防止受体饱和，和4. MUP充当激活受体的转换器。该提议的总体假设是，鼻MUP用于选择性地结合生物学上有意义的疏水分子，并且对于气味检测和随后的行为至关重要。该提案的主要目标是应用遗传学、生理学和行为学的综合方法来阐明鼻MUP在哺乳动物化学通讯中的生理作用以及这些化合物影响生物学相关社会行为的机制。这种研究外周感受器事件的方法可能会为化学感觉的研究开辟新的途径，并扩大我们对嗅觉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.