Retinoic Acid Signaling in Salivary Gland Organogenesis

唾液腺器官发生中的视黄酸信号传导

• 批准号: 9396002
• 负责人: Melissa A Metzler
• 金额: $ 5.71万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396002
• 关键词: All-Trans-Retinol; Alleles; Autoimmune Diseases; Biological Assay; Biomedical Research; Cell Count; Cell Differentiation process; Cell Maintenance; Chemicals; Chronic; Clinical; Communication; Data; Development; Digestion; Embryo; Embryonic Development; Enzymes; Epithelial; Epithelium; Equilibrium; Experimental Models; Future; Gene Expression; Genes; Gland; Growth; In Vitro; Investigation; Kidney; Knock-out; Knowledge; LacZ Genes; Ligands; Lubrication; Lung; Mandible; Mediating; Metabolism; Monitor; Morphogenesis; Mus; Natural regeneration; Nerve; Neural Crest; Neurons; Nuclear Family; Nuclear Receptors; Oral cavity; Oral health; Organ; Organogenesis; Oxides; Pancreas; Patients; Phase; Physical condensation; Preparation; Process; Production; Quality of life; Radiation therapy; Reaction; Reporter; Research; Research Personnel; Retinoic Acid Receptor; Retinol Metabolism Pathway; Role; Saliva; Salivary; Salivary Glands; Schwann Cells; Signal Transduction; Signaling Molecule; Stem cells; Structure of parasympathetic ganglion; Submandibular gland; Supplementation; Surface; System; Testing; Tissues; Training; Transgenic Organisms; Tretinoin; Vitamin A; Xerostomia; antimicrobial; career; chorda tympani; embryo tissue; experience; gland development; hindbrain; in vitro Assay; inhibitor/antagonist; innovation; migration; neuron development; neuronal survival; novel; oxidation; remineralization; salivary assay

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.

抽象的 了解胚胎在发育过程中如何构建器官对于为研究提供信息至关重要 体外再生组织。目前临床上需要为以下患者再生唾液腺： 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 口干症（口干）会导致口腔健康和生活质量急剧下降。建设能力 这些患者的功能性腺体将使唾液恢复到口腔，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 再矿化。 目前许多唾液腺发育研究已经阐明了唾液腺发育所需的信号分子 对于几个重要的过程，如分支形态发生、管腔形成、细胞分化和 祖细胞维护。该领域的研究还表明，早期唾液腺发育 依赖于上皮细胞和密切相关的副交感神经节（PSG）的削弱。 然而，人们对腺体发育的最早阶段知之甚少，也没有进行任何研究 控制唾液腺起始或 PSG 形成所需的信号分子。知识上的差距 可能是由于缺乏腺体器官发生最早阶段的实验模型。 为了准备这个提案，我建立了一种利用小鼠的新型离体培养系统 胚胎组织来测定唾液腺的起始。这是该领域的一个重要发展，因为它允许 研究人员能够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 表明 RA 信号传导对于下颌下腺 (SMG) 的启动和发育是必需的 副交感神经节（PSG）。阻断 RA 信号传导会抑制腺芽萌生，反之， 补充视黄醇（维生素 A）可增强起始作用。此外，我已经确定了 当 RA 信号传导被阻断时，初始 PSG 会减少，细胞数量也会减少。在这个提案中，我将 研究视黄醇氧化酶 RDH10 的维生素 A 代谢在 SMG 启动中的作用 上皮细胞，以及 RA 信号传导对 PSG 形成的作用。