Olfactory Support Cells

描述（由申请人提供）：嗅觉上皮的支持细胞很少受到直接关注，但有几条证据表明，它们对于维持或调节嗅觉感觉神经细胞、嗅觉感觉神经细胞的持续替代以及允许气味检测的局部环境至关重要。对两种主要的支持细胞，支持细胞和鲍曼腺细胞，缺乏详细的分子理解。幸运的是，我们已经开发出一种小鼠品系，使我们能够提取两种分离的细胞样本：一种高度富集支持细胞，另一种富集鲍曼腺腺泡细胞。因此，目的1将研究两个支持细胞转录组是否显示假设在这些支持细胞中活跃的生物过程的过度表达：外来化学物质的清除，细胞粘附，死亡细胞的清除，分泌和某些细胞信号传导途径。这一目标的成果还将包括一个超过10，000个基因在支持细胞和鲍曼腺泡细胞中表达概率的数据库。目标2更深入地研究了我们假设的支持细胞控制吞噬作用的机制，这是这些细胞为数不多的记录功能之一。我们推测，通过受体酪氨酸激酶Tyro3的信号调节支持细胞对垂死神经细胞的清除。总的来说，该项目是朝着全面了解嗅上皮中基因表达模式迈出的又一步，并将确定该组织中很少研究的支持细胞中存在的大多数功能。此外，这些实验与嗅觉功能的年龄依赖性丧失有关，因为已知几种其他组织的支持细胞中Tyro3受体家族信号传导的缺陷会导致年龄相关的疾病，例如视网膜变性。公共卫生相关性：嗅觉系统已经进化到可以检测和区分数千种不同的挥发性化学物质，部分原因是产生了有利的微环境，并保持了即使在衰老时也能替换受损嗅觉神经细胞的能力。研究上皮细胞的支持细胞如何有助于气味检测和神经细胞替代，必将提高我们对细胞相互作用如何有助于嗅觉系统在动物一生中发挥作用的能力的理解。该项目研究上皮支持细胞的分子能力，以及支持细胞清除垂死神经细胞为新神经细胞让路的假设机制。

Description (provided by applicant): The support cells of the olfactory epithelium have received little direct attention, yet several lines of evidence indicate that they are critical for maintaining or regulating the olfactory sensory nerve cells, the ongoing replacement of olfactory sensory nerve cells, and the local environment that allows odor detection. A detailed molecular understanding of the two major types of support cells, sustentacular cells and Bowman's gland cells, is lacking. Fortuitously, we have developed a mouse strain that will allow us to extract two dissociated cell samples: One highly enriched for sustentacular cells, the other for Bowman's gland acinar cells. Aim 1 will therefore investigate whether two support cell transcriptomes show overrepresentation of biological processes hypothesized to be active in these support cells: Clearance of foreign chemicals, cell adhesion, clearance of dying cells, secretion, and certain cell signaling pathways. The outcome of this aim will also include a database of the probability of expression in sustentacular cells and Bowman's gland acinar cells for more than 10,000 genes. Aim 2 delves more deeply into a mechanism we hypothesize controls phagocytosis by sustentacular cells, one of the few documented functions of these cells. We hypothesize that signaling through the receptor tyrosine kinase Tyro3 regulates clearance of dying nerve cells by sustentacular cells. Overall, this project is another step toward a complete understanding of gene expression patterns in the olfactory epithelium and will identify most functions present in the little-studied support cells of this tissue. In addition, these experiments are relevant to age-dependent loss of olfactory function because deficits in Tyro3 receptor family signaling in the support cells of several other tissues are known to lead to age-related disorders, such as retinal degeneration. PUBLIC HEALTH RELEVANCE: The olfactory system has evolved to detect and discriminate many thousands of distinct volatile chemicals, in part by generating a favorable microenvironment and retaining the ability to replace damaged olfactory nerve cells even as aging occurs. Investigating how the support cells of the epithelium contribute to odor detection and nerve cell replacement is bound to improve our understanding of how cellular interactions contribute to the ability of the olfactory system to function throughout an animal's life span. This project investigates the molecular capabilities of the support cells of the epithelium and a hypothesized mechanism by which support cells clear dying nerve cells to make way for new nerve cells.