Xenobiotics detection in olfactory epithelium

描述（由申请人提供）：哺乳动物鼻腔中的主要嗅上皮（MOE）具有两种不同的功能。首先，MOE检测到空气中几乎无限的气味分子，并启动嗅觉。其次，MOE代谢和清除吸入的外来生物，包括高浓度的气味刺激物、空气污染物和微生物。后一种情况下，上皮防御功能至关重要，不仅可以维持MOE的正常功能，还可以通过限制外来生物进入这些器官来保护重要器官，如下气道、肺和脑。然而，关于外源物检测机制和随后协调MOE防御的途径的基本信息缺失，这限制了我们对与外源物损伤相关的呼吸系统疾病嗅觉功能障碍的理解。我们最近在MOE中发现了一群表达瞬时受体电位m5的微绒毛细胞（trpM5-MCs）。我们的初步研究表明，trpM5-MCs具有化学敏感性和胆碱能性，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Ca2+水平。我们假设trpM5-MCs检测异种生物并随后协调MOE防御网络的活动。我们将通过以下四个具体目标来检验这一中心假设。目的1将确定trpM5-MCs的反应谱和外源性检测所需的关键要素。目的2和3将描述允许trpM5-MCs协调和调节MOE防御网络活动的细胞内和细胞间途径。目的4将确定trpM5-MCs缺陷小鼠MOE的形态学和功能缺陷。提出这项研究的基本原理是，了解外源性检测机制和导致外源性清除调节的途径对于理解上皮防御非常重要，并将使创新方法能够针对外源性相关呼吸系统疾病的初始发展。我们期望获得关于外源性检测机制和后续途径的基本知识，协调和调节MOE防御。我们还预计，trpM5-MCs中外源检测缺陷将损害MOE防御网络，导致上皮结构和功能缺陷。这项提议的研究是创新的，因为它代表了一种新的方法来理解外源性接触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诱导的病理变化奠定了基础，这些病理变化可能最终导致外源性暴露相关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.