A MODEL FOR MUCOUS GLAND EXOCRINE CELL EXPRESSION

干扰阻止唾液腺分泌的神经激活导致萎缩和伴随的表达外分泌细胞表型的细胞损失。因此，成人腺体外分泌细胞的表型表达部分取决于自主神经在分泌激活过程中释放的神经递质所调节的机制。阐明这些神经介导的机制将为诱导和维持移植（或移植）唾液腺细胞（或组织）的外分泌细胞表型表达提供见解，作为细胞治疗的一部分，以增强受损唾液腺的外分泌功能。不幸的是，由于缺乏适当的体外模型系统，如高度分化的细胞系或唾液外分泌细胞的原代培养，阻碍了我们对这些机制的理解。我们的实验室专注于唾液黏液腺的调节。特别是大鼠的舌下腺体。这些腺体。与其他唾液腺不同。主要接受副交感神经，通过激活毒蕈碱胆碱能受体刺激腺泡黏液细胞的分泌液和外分泌。在一项初步研究中，慢性全身给药毒蕈碱拮抗剂导致黏液腺萎缩，黏液细胞表型的表达明显选择性减少。我们已经开发了一种直接将拮抗剂递送到舌下腺的方案，这将为研究毒蕈碱介导的机制控制成人腺体中粘液细胞表型表达的维持提供独特的机会。此外，在减少黏液细胞表型表达后去除拮抗剂有望启动体内再生正常黏液腺泡结构的机制。因此，我们建议对该模型系统进行初步评估。特别。我们计划应用形态计量学和生化标准来确定黏液表达随时间的变化。浆液性新月。慢性阿托品对大鼠舌下腺导管细胞的影响；2)确定去除拮抗剂后每种细胞类型的再生能力。使用该模型的研究获得的未来信息可能最终用于使用新的细胞疗法治疗口干症患者，如基因工程移植组织或设计用于持续表达功能性外分泌细胞表型的祖细胞。

Perturbations which block the neural activation of salivary gland secretion lead to atrophy and the concomitant loss of cells expressing exocrine cell phenotypes. Thus, phenotypic exocrine cell expression in adult glands is dependent, in part, upon mechanisms regulated by neurotransmitters released by autonomic nerves during activation of secretion. Elucidation of these neural mediated mechanisms will provide insights into efforts to induce and maintain expression of exocrine cell phenotypes of implanted (or transplanted) salivary cells (or tissue) as part of cell-based therapies to enhance exocrine function of damaged salivary glands. Unfortunately, advancement in our understanding of these mechanisms is hindered by the absence of appropriate in-vitro model systems such as highly differentiated cell lines or primary cultures of salivary exocrine cells. Our laboratory is focused on the regulation of salivary mucous glands. specifically rat sublingual glands. These glands. in contrast to other salivary glands. receive predominantly parasympathetic nerves which stimulate both fluid and exocrine secretion of acinar mucous cells through activation of muscarinic cholinergic receptors. In a preliminary study, chronic systemic administration of muscarinic antagonist resulted in mucous gland atrophy with the apparent selective diminution of expression of the mucous cell phenotype. We have since developed a protocol to deliver antagonist directly to sublingual glands which will provide the unique opportunity to study muscarinic mediated mechanisms controlling maintenance of mucous cell phenotypic expression in adult glands. In addition, removal of antagonist after diminishment of mucous cell phenotypic expression is expected to initiate mechanisms to regenerate normal mucous acinar structures, in-vivo. We therefore propose to initially evaluate this model system. Specifically. we plan to apply morphometric and biochemical criteria to l) determine changes with time in the expression of mucous. serous demilune. and ductal cells of rat sublingual glands in response to chronic atropine treatment; and to 2) determine the regenerative capacity of each cell type upon removal of antagonist. Future information derived from studies using this model may ultimately be used to treat xerostomic patients with new cell-based therapies such as genetically engineered transplant tissue or progenitor cells designed to continually express functional exocrine cell phenotypes.