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上皮的不同细胞类型的发育中调节细胞命运决定的信号传导机制。嗅上皮是一种感觉上皮，其不断地从祖细胞更新神经元，并且可以在损伤后再生。嗅上皮的发育涉及祖细胞的建立和维持、嗅感受神经元的神经发生和支持细胞的形成。然而，这些细胞命运决定的调节尚不清楚。简单，明确的架构和可用性的细胞类型和分化状态的特异性标志物，使嗅上皮一个很好的模型，用于研究神经发生和祖细胞调节的过程。有证据表明，骨形态发生蛋白（BMP）信号参与嗅觉上皮的发育。这项研究将首先确定哪些BMP信号成分存在于嗅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信号传导组分中的遗传功能丧失突变体，以确定特定BMP信号传导如何调节祖细胞维持和神经发生。这将涉及分析突变体在一系列细胞类型和分化状态特异性标志物、细胞增殖和细胞死亡中的变化。最终，这项研究应该提供深入了解BMP信号如何调节这些过程，它将奠定基础，为未来的研究信号通路的相互作用和再生的调节。嗅上皮包含数千个神经元，它们可以感知环境中的挥发性化学物质，并且在整个生命过程中更新这些神经元，并且可以在受伤时再生。然而，调节该组织建立的分子和细胞机制知之甚少。了解再生组织是如何在分子和细胞水平上建立的，对于了解如何处理神经组织的损伤和疾病具有很大的希望。

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.