A MODEL FOR MUCOUS GLAND EXOCRINE CELL EXPRESSION

干扰会阻碍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丢失。因此，成体腺体表型外分泌细胞的表达在一定程度上依赖于分泌激活时自主神经释放的神经递质调节的机制。阐明这些神经介导的机制将为诱导和维持植入(或移植)唾液细胞(或组织)的外分泌细胞表型的表达提供洞察，作为基于细胞的治疗的一部分，以增强受损唾液腺的外分泌功能。不幸的是，由于缺乏合适的体外模型系统，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粘液腺的调节。特别是大鼠的舌下腺。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M胆碱能受体刺激腺泡粘液细胞的液体和外分泌分泌。在一项初步研究中，长期全身给药M受体拮抗剂导致粘液腺萎缩，粘液细胞表型的表达明显选择性减少。自那以后，我们开发了一种将拮抗剂直接输送到舌下腺的方案，这将提供一个独特的机会来研究毒扁豆碱介导的控制成人腺体粘液细胞表型表达的机制。此外，在粘液细胞表型表达减弱后去除拮抗剂有望在体内启动再生正常粘液腺泡结构的机制。因此，我们建议对这一模式系统进行初步评估。具体地说。我们计划应用形态计量学和生化标准来确定粘液的表达随时间的变化。严肃的半月形。和大鼠舌下腺导管细胞对阿托品慢性治疗的反应；以及2)确定每种细胞类型在去除拮抗剂后的再生能力。使用该模型的研究得出的未来信息可能最终用于治疗干燥症患者，采用基于细胞的新疗法，例如设计为持续表达功能性外分泌细胞表型的基因工程移植组织或祖细胞。

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.