Xenobiotics detection in olfactory epithelium

描述（由申请人提供）：哺乳动物鼻腔中的主要嗅觉上皮（莫伊）具有两种不同的功能。首先，莫伊检测几乎无限数量的空气中的气味分子，并启动嗅觉。第二，莫伊代谢并去除吸入的异生物质，包括高水平的气味刺激物、空气污染物和微生物。后者，上皮防御功能是至关重要的，不仅对于维持莫伊的适当功能，而且对于通过限制外源性物质进入这些器官来保护重要器官，例如下呼吸道、肺和脑。然而，有关异生物质检测机制和协调莫伊防御的后续途径的基本信息缺失，这限制了我们对与异生物质损伤相关的呼吸系统疾病中嗅觉功能障碍的理解。我们最近已经确定了一个人口的瞬时受体电位M5表达微绒毛细胞（trpM 5-MCs）的莫伊。我们的初步研究表明，trpM 5-MCs是化学敏感性和胆碱能，这意味着它们能够释放乙酰胆碱（ACh）来调节邻近支持细胞的细胞内Ca 2+水平。我们假设，trpM 5-MCs检测外源性物质，随后协调活动的莫伊防御网络。我们将通过追求以下四个具体目标来检验这一中心假设。目的1将确定trpM 5-MCs的响应曲线和异源生物质检测所需的关键要素。目的2和3将表征允许trpM 5-MC协调和调节莫伊防御网络活性的细胞内和细胞间途径。目的4将确定具有缺陷trpM 5-MC的小鼠的莫伊的形态和功能缺陷。拟议研究的基本原理是，异生物质检测机制和异生物质清除调节途径的知识对于理解上皮防御非常重要，并将使创新方法能够针对异生物质相关呼吸道疾病的初步发展。我们希望获得有关异生检测机制和协调和调节莫伊防御的后续途径的基础知识。我们还预期trpM 5-MCs中异生物质检测的缺陷将损害莫伊防御网络，导致上皮的结构和功能缺陷。这项研究是创新的，因为它代表了一种新的方法来了解外源性暴露和呼吸系统疾病之间的关系。这些研究的意义在于，它们为未来研究外源性物质诱导的病理变化奠定了基础，这些病理变化最终可能导致与外源性物质相关的嗅觉功能障碍和呼吸系统疾病的新治疗方法。

DESCRIPTION (provided by applicant): The main olfactory epithelium (MOE) in the mammalian nasal cavity serves two distinct functions. First, the MOE detects almost an infinite number of airborne odor molecules and initiates the sense of smell. Second, the MOE metabolizes and removes inhaled xenobiotics, which include high levels of odorous irritants, air pollutants and microorganisms. This latter, epithelial defense function is critically important, no only for maintaining the proper function of the MOE, but also for protecting vital organs, such as the lower airway, lungs and brain by limiting xenobiotic access to these organs. However, fundamental information about mechanisms of xenobiotic detection and the subsequent pathways coordinating MOE defense is missing, which limits our understanding of olfactory dysfunction in respiratory diseases associated with xenobiotic insults. We recently have identified a population of transient receptor potential M5-expressing microvillous cells (trpM5-MCs) in the MOE. Our initial study shows that trpM5-MCs are chemosensitive and cholinergic, meaning they are capable of releasing acetylcholine (ACh) to modulate intracellular Ca2+ levels of neighboring supporting cells. We hypothesize that trpM5-MCs detect xenobiotics and subsequently coordinate activities of the MOE defense network. We will test this central hypothesis by pursuing the following four specific aims. Aim 1 will determine the response profiles of trpM5-MCs and the key elements necessary for xenobiotic detection. Aims 2 and 3 will characterize intracellular and intercellular pathways that allow trpM5-MCs to coordinate and regulate MOE defense network activities. Aim 4 will determine morphological and functional deficits in the MOE of mice with defective trpM5-MCs. The rationale for the proposed research is that knowledge of the mechanisms of xenobiotic detection and the pathways leading to regulation of xenobiotic clearance is important for the understanding of epithelial defense and will enable innovative approaches to target the initial development of xenobiotic-associated respiratory diseases. We expect to obtain fundamental knowledge about xenobiotic detection mechanisms and subsequent pathways that coordinate and regulate MOE defense. We also expect that defects in xenobiotic detection in trpM5-MCs will impair the MOE defense network, resulting in structural and functional deficits in the epithelium. This proposed research is innovative, because it represents a new approach to understand the relationship between xenobiotic exposure and respiratory diseases. The significance of these studies is that they lay the groundwork for future research on xenobiotic-induced pathological changes that may ultimately lead to new treatments for xenobiotic exposure-related olfactory dysfunction and respiratory diseases.