Signals That Regulate Olfactory Epithelial Development

描述（由申请人提供）：本研究项目的长期目标是了解调节祖细胞和神经发生的细胞事件。本研究将利用遗传学的方法来了解在嗅觉上皮不同细胞类型的发育过程中调控细胞命运决定的信号机制。嗅觉上皮是一种感觉上皮，它能不断地从祖细胞中更新神经元，并能在损伤后再生。嗅觉上皮的发育包括祖细胞的建立和维持、嗅觉受体神经元的神经发生以及支撑细胞的形成。然而，这些细胞命运决定的调控机制尚不清楚。嗅觉上皮结构简单，结构明确，并且具有细胞类型和分化状态特异性标记物，这使得嗅觉上皮成为研究神经发生和祖细胞调节过程的良好模型。有证据表明骨形态发生蛋白（Bone Morphogenetic Protein， BMP）信号参与了嗅觉上皮的发育。本研究将首先确定哪些BMP信号成分存在于嗅觉上皮的特定细胞类型中，其次，将评估BMP信号的激活。随后，将研究特定BMP信号成分的基因功能缺失突变，以确定特定BMP信号如何调节祖细胞维持和神经发生。这将包括分析突变体在一系列细胞类型和分化状态特异性标记、细胞增殖和细胞死亡中的变化。最终，本研究将提供BMP信号如何调节这些过程的信息，并为未来信号通路相互作用和再生调控的研究奠定基础。嗅觉上皮包含成千上万的神经元，这些神经元可以感知环境中的挥发性化学物质，并在整个生命过程中更新这些神经元，并在受伤时再生。然而，调控这种组织建立的分子和细胞机制尚不清楚。了解再生组织是如何在分子和细胞水平上建立起来的，对于如何处理神经组织的损伤和疾病有很大的希望。

DESCRIPTION (provided by applicant): The long-term objective of this research project is to understand the cellular events that regulate progenitor cells and neurogenesis. This study will use genetic approaches to understand the signaling mechanisms that regulate the cell fate decisions in the development of the diverse cell-types of the olfactory epithelium. The olfactory epithelium is a sensory epithelium that constantly renews neurons from progenitor cells and can regenerate upon injury. The development of the olfactory epithelium involves the establishment and maintenance of progenitor cells, neurogenesis of olfactory receptor neurons, and formation of support cells called sustentacular cells. However, the regulation of these cell-fate decisions is not understood. The simple, well-defined architecture and the availability of cell-type and differentiation-state specific markers make the olfactory epithelium an excellent model for studying the processes of neurogenesis and progenitor cell regulation. There is evidence that Bone Morphogenetic Protein (BMP) signaling is involved in olfactory epithelial development. This study will first define which BMP signaling components are present in specific cell types of the olfactory epithelium, and secondly, activation of BMP signaling will be assessed. Subsequently, genetic loss-of-function mutants in specific BMP signaling components will be investigated to determine how specific BMP signaling regulates progenitor maintenance and neurogenesis. This will involve analyzing mutants for changes in a range of cell-type and differentiation-state specific markers, cell proliferation, and cell death. Ultimately this study should provide insight into how BMP signaling regulates these processes, and it will lay the foundation for future studies on signaling pathway interactions and the regulation of regeneration. The olfactory epithelium contains thousands of neurons that sense volatile chemicals in the environment, and it renews these neurons throughout life and can regenerate upon injury. However, the molecular and cellular mechanisms that regulate the establishment of this tissue are poorly understood. Understanding how a regenerative tissue is established at the molecular and cellular level has great promise for gaining insights into how to deal with damage and disease of neural tissue.