SALIVARY GLAND SECRETION MECHANISMS DURING NORMAL AND ALTERED FUNCTIONAL STATES

正常和功能改变状态下的唾液腺分泌机制

• 批准号: 6289664
• 负责人: BRUCE J BAUM
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289664
• 关键词: Adenoviridae; acinar cell; epithelium; gene therapy; laboratory rat; recombinant virus; saliva; salivary disorder; salivary glands; salivation; tissue /cell culture; transfection; water channel

The health of the oral cavity is maintained by salivary secretions. Our past studies focused on understanding mechanisms of saliva formation, their alteration during pathology, and developing novel methods to treat salivary dysfunction. During this reporting period we continued to utilize gene transfer technology to alter salivary epithelial cells to address clinical and biological questions. Specifically, we focused on two major problems resulting from use of recombinant adenoviral vectors: transient transgene expression and a potent immune response. To extend expression we have used recombinant adeno-associated virus vectors, and developed a unique hybrid vector incorporating both adenoviral and retroviral elements. Both approaches lead to more stable expression in rodent glands. Two ways to manipulate the immune response were tried; a drug, clodronate, to deplete glands of phagocytic cells, and coadministration of vectors encoding either IL-4 or IL-10. Both methods were unsuccessful. We showed that transgenes contain sorting signals recognized by glands in vivo, that lead to specific patterns of polarized protein secretion. We also made progress towards the development of an orally implantable, first generation artificial salivary gland. - salivary glands, gene therapy, adenovirus, AAV, hybrid vectors, radiation damage, Sjogren's syndrome, secretion, biomimetics

口腔的健康是由唾液分泌物维持的。我们过去的研究集中在理解唾液形成的机制，病理学期间的改变以及开发用于治疗唾液功能障碍的新方法。在此报告期间，我们继续利用基因转移技术改变唾液上皮细胞来解决临床和生物学问题。具体而言，我们专注于使用重组腺病毒载体引起的两个主要问题：瞬时转基因表达和有效的免疫反应。为了扩展表达，我们使用了重组腺相关的病毒载体，并开发了一种独特的杂化载体，该杂化载体同时结合了腺病毒和逆转录病毒元件。两种方法都导致啮齿动物腺体表达更稳定。尝试操纵免疫反应的两种方法。一种药物，可在耗尽吞噬细胞的腺体，以及编码IL-4或IL-10的矢量的腺体。两种方法都没有成功。我们表明，转基因包含由体内腺体识别的分类信号，这导致了极化蛋白质分泌的特定模式。我们还取得了进步，以开发口服的，第一代人造唾液腺。 - 唾液腺，基因疗法，腺病毒，AAV，杂化载体，辐射损伤，Sjogren综合征，分泌，仿生学