Signals That Regulate Olfactory Epithelial Development

描述(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。这项研究将使用遗传学方法来了解在不同细胞类型的嗅觉上皮发育过程中调节细胞命运决定的信号机制。嗅觉上皮是一种感觉上皮，它不断地更新前体细胞中的神经元，并能在损伤后再生。嗅觉上皮的发育包括前体细胞的建立和维持，嗅觉感受器神经元的神经发生，以及支持细胞的形成。然而，对这些细胞命运决定的调节还不清楚。简单、明确的结构以及细胞类型和分化状态特异性标记物的可获得性使嗅觉上皮成为研究神经发生和祖细胞调节过程的极佳模型。有证据表明，骨形态发生蛋白(BMP)信号转导参与了嗅觉上皮的发育。这项研究将首先确定在嗅觉上皮的特定细胞类型中存在哪些BMP信号成分，其次，将评估BMP信号的激活。随后，将对特定BMP信号成分中的遗传功能丧失突变进行调查，以确定特定BMP信号如何调节祖细胞维持和神经发生。这将包括分析突变株在一系列细胞类型和分化状态特定标记、细胞增殖和细胞死亡方面的变化。最终，这项研究将为BMP信号如何调控这些过程提供洞察力，并将为未来信号通路相互作用和再生调控的研究奠定基础。嗅觉上皮含有数以千计的神经元，这些神经元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，调控这一组织建立的分子和细胞机制却知之甚少。了解再生组织是如何在分子和细胞水平上建立的，对于深入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.