Xenobiotics detection in olfactory epithelium

描述(申请人提供)：哺乳动物鼻腔中的主要嗅觉上皮(MOE)有两种截然不同的功能。首先，MOE探测到几乎无限数量的空气中的气味分子，并启动嗅觉。其次，能源部代谢并去除吸入的异生物质，其中包括高水平的气味刺激物、空气污染物和微生物。后者，上皮防御功能至关重要，不仅对于维持MOE的正常功能，而且对于通过限制异物进入这些器官来保护重要器官，如下呼吸道、肺和脑也是至关重要的。然而，关于异物检测的机制和随后协调MOE防御的途径的基本信息仍然缺乏，这限制了我们对与异物侮辱相关的呼吸系统疾病中嗅觉功能障碍的理解。我们最近在MOE中发现了一组瞬时受体潜能M5表达的微绒毛细胞(Trpm5-MCs)。我们的初步研究表明，Trpm5-MCs是化疗敏感的和胆碱能的，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钙水平。我们假设Trpm5-MCs检测到外源物质，并随后协调MOE防御网络的活动。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Trpm5-MCs的反应谱和检测外源生物所需的关键元件。AIMS 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通路。目的4将确定Trpm5-MCs缺陷小鼠的MOE的形态和功能缺陷。这项拟议研究的基本原理是，了解外源生物检测的机制和导致外源生物清除的调节途径对于理解上皮防御非常重要，并将使创新的方法能够针对外源生物相关呼吸系统疾病的最初发展。我们期望获得关于外源生物检测机制以及协调和调节MOE防御的后续途径的基础知识。我们还预计，Trpm5-MCs中异物检测的缺陷将损害MOE防御网络，导致上皮结构和功能缺陷。这项拟议的研究是创新的，因为它代表了一种新的方法来理解异物暴露与呼吸系统疾病之间的关系。这些研究的意义在于，它们为未来研究异种生物引起的病理变化奠定了基础，最终可能导致异种生物暴露相关的嗅觉障碍和呼吸系统疾病的新疗法。

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.