A MODEL FOR MUCOUS GLAND EXOCRINE CELL EXPRESSION

粘液腺外分泌细胞表达模型

• 批准号: 6379983
• 负责人: DAVID JOHN CULP
• 金额: $ 3.99万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6379983
• 关键词: acinar cell; atrophy; atropine; biological models; drug delivery systems; endocrine pharmacology; laboratory rat; model design /development; mucus; muscarinic receptor; northern blottings; regeneration; sublingual gland; western blottings

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.

阻断唾液腺分泌的神经激活的扰动导致萎缩和表达外分泌细胞表型的细胞的伴随损失。因此，表型外分泌细胞在成人腺体的表达是依赖，部分，在分泌激活过程中自主神经释放的神经递质调节的机制。这些神经介导的机制的阐明将提供对作为基于细胞的疗法的一部分的植入（或移植）的唾液细胞（或组织）的外分泌细胞表型的诱导和维持表达的努力的见解，以增强受损唾液腺的外分泌功能。不幸的是，我们对这些机制的理解的进展受到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物的阻碍。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，其通过激活毒蕈碱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，长期全身给予毒蕈碱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。此后，我们开发了一种将拮抗剂直接递送至舌下腺的方案，这将为研究控制成人腺体中粘液细胞表型表达的维持的毒蕈碱介导的机制提供独特的机会。此外，预期在粘液细胞表型表达减少后去除拮抗剂可启动体内再生正常粘液腺泡结构的机制。因此，我们建议对该模型系统进行初步评估。具体来说我们计划应用形态测量和生物化学标准来1）确定粘液表达随时间的变化。浆液性半月板。和大鼠舌下腺的导管细胞对慢性阿托品治疗的反应;和2）测定除去拮抗剂后每种细胞类型的再生能力。从使用该模型的研究中获得的未来信息可能最终用于用新的基于细胞的疗法治疗口干燥症患者，例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。