Olfactory Support Cells

描述(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，它们对维持或调节嗅觉神经细胞、正在进行的嗅觉神经细胞的替换以及允许气味检测的局部环境至关重要。对支持细胞的两种主要类型，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，它将允许我们提取两个分离的细胞样本：一个高度浓缩的支持细胞，另一个用于鲍曼腺腺泡细胞。因此，目标1将研究两个支持细胞转录本是否过度表达了假设在这些支持细胞中活跃的生物学过程：清除外来化学物质、细胞黏附、清除垂死细胞、分泌和某些细胞信号通路。这一目标的结果还将包括一个超过10,000个基因在支持细胞和鲍曼腺腺泡细胞中表达概率的数据库。Aim 2更深入地研究了一种我们假设的通过支持细胞控制吞噬作用的机制，这是为数不多的已知的这些细胞的功能之一。我们假设，通过受体酪氨酸激酶Tyro3的信号调节支持细胞对死亡神经细胞的清除。总体而言，该项目是朝着全面了解嗅觉上皮细胞中的基因表达模式又迈进了一步，并将确定该组织中鲜有研究的支持细胞中存在的大多数功能。此外，这些实验与年龄相关的嗅觉功能丧失有关，因为已知其他几个组织的支持细胞中Tyro3受体家族信号的缺陷会导致与年龄相关的疾病，如视网膜退化。与公共健康相关：嗅觉系统已经进化成能够检测和辨别数千种不同的挥发性化学物质，部分是通过产生良好的微环境，并保持即使在衰老发生时仍能替换受损的嗅神经细胞的能力。研究上皮的支持细胞如何对气味检测和神经细胞替换做出贡献，肯定会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，以及支持细胞清除濒临死亡的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.