Retinoic Acid Signaling in Salivary Gland Organogenesis

摘要 了解胚胎在发育过程中如何构建器官对于研究 在体外再生组织。目前临床上需要为患有以下疾病的患者再生唾液腺： 由于放射治疗或自身免疫性疾病而遭受永久性腺体损伤。由此产生的慢性 口腔干燥症（口干）导致口腔健康和生活质量的急剧下降。构建的能力 这些患者的功能腺将恢复唾液到口腔，其中包括许多有益的 涉及抗菌保护、pH平衡、消化、润滑等功能的成分， 商业化。 目前对唾液腺发育的许多研究已经阐明了唾液腺发育所必需的信号分子。 几个重要的过程，如分支形态发生，管腔形成，细胞分化， 祖细胞维持该领域的研究还表明，早期唾液腺发育是 依赖于上皮和来自密切相关的副交感神经节（PSG）的神经支配。 然而，对腺体发育的最早阶段知之甚少，也没有进行过研究 控制唾液腺启动或PSG形成所需的信号分子。知识上的差距 可能是由于缺乏腺器官发生的最早阶段的实验模型。 在准备这个建议，我已经建立了一个新的离体培养系统，利用小鼠 胚胎组织以测定唾液腺起始。这是该领域的一个重要发展，因为它允许 研究人员可以回答他们以前无法回答的问题。通过这个系统，我已经生成了初步数据 显示RA信号传导是下颌下腺（SMG）启动和发育所必需的。 副交感神经节（PSG）。阻断RA信号传导抑制腺芽的形成，反之， 补充视黄醇（维生素A）增强启动。此外，我已经确定， 当RA信号传导被阻断时，初始PSG减少，具有更少数量的小区。在这份提案中，我将 研究维生素A代谢的视黄醇氧化酶RDH 10在SMG启动中的作用 上皮，和RA信号传导对PSG形成的作用。

Abstract Understanding how an embryo builds an organ during development is essential to inform studies into regenerating tissue in vitro. There is currently a clinical need to regenerate salivary glands for patients who have suffered permanent gland damage due to radiation therapy or autoimmune disease. The resulting chronic xerostomia (dry mouth) leads to a sharp decline in oral health and quality of life. The ability to construct functioning gland for these patients would restore saliva to the oral cavity, which includes many beneficial components involved in functions such as antimicrobial protection, pH balance, digestion, lubrication, and remineralization. Many current studies in salivary gland development have elucidated the signaling molecules necessary for several important processes such as branching morphogenesis, lumen formation, cell differentiation, and progenitor cell maintenance. Studies in the field have also shown that early salivary gland development is dependent on both the epithelium and enervation from the closely associated parasympathetic ganglion (PSG). However, very little is known about the earliest stages of gland development, and no studies have been done on the signaling molecules needed to control salivary gland initiation or PSG formation. The gap in knowledge is likely due to the lack of experimental models for the earliest phases of gland organogenesis. In preparation for this proposal, I have established a novel ex vivo culture system utilizing mouse embryo tissues to assay salivary gland initiation. This is an important development for the field in that it allows researchers to answer questions they could not before. With this system, I have generated preliminary data showing that RA signaling is required for submandibular gland (SMG) initiation and development of the parasympathetic ganglion (PSG). Blocking RA signaling represses gland bud initiation, and, conversely, supplementation with retinol (vitamin A) enhances initiation. Moreover, I have identified that the size of the initial PSG is reduced, with a fewer number of cells, when RA signaling is blocked. In this proposal, I will investigate the role of vitamin A metabolism by the retinol oxidizing enzyme RDH10 in initiation of the SMG epithelium, and the role of RA signaling on PSG formation.