REGULATION OF GLANDULAR MUCOUS CELL SECRETION

描述(改编自研究人员摘要)：唾液粘蛋白 糖蛋白有助于保护口腔的硬表面和软表面。 粘蛋白很大程度上是由粘液腺分泌的(例如，舌下和 唇腺)，主要由粘液腺泡细胞组成。 粘蛋白利用率的降低与唾液腺的影响有关 功能减退(即龋齿增加和缺乏润滑剂)。 目前治疗肾功能减退的方法包括全身应用 M胆碱能激动剂，匹罗卡品，直接刺激残留 有功能的唾液分泌细胞。不幸的是，匹罗卡品 对五种不同的M受体亚型(S)的非特异性 可能解释在临床试验中观察到的多种不良副作用。 目前，制药公司正试图开发针对亚型的 激动剂以及靶向给药系统，用于持续或 受管制的药物释放。很快，就有可能在当地交付一种 M受体激动剂(亚型或非亚型选择性)以增强 淋巴功能减退患者的唾液分泌。一种药物可能 从而以调节的方式以更高和更有效的剂量递送， 但副作用减少，患者依从性提高。它是, 因此，必须了解分泌细胞受体是如何 受暴露于激动剂的调节，两者都与激动剂浓度有关 和暴露时间，以提供一个框架，以基础实验性治疗 未来临床试验中的治疗方案。鉴于粘蛋白在人体内的重要性 口腔保护与M受体的主要作用 在诱导粘液细胞分泌方面，有人建议进行研究以确定 激动剂对大鼠脑内M受体功能和表达的调节 唾液粘液腺。作为我们的模型系统，大鼠的舌下腺， 类似于人类的许多粘液腺，将被使用。具体来说， 隔离的腺泡结构将用于：a.)测定腺泡外分泌 对持续的激动剂挑战作出反应；b.)测定 胆碱能受体保留激活粘蛋白分泌功能；澄清以下问题 持续激动剂激发之间的数量和时间关系 以及受体隔离和下调；d.定义机制 负责激动剂诱导的受体下调；以及e)测定 受体表达和外分泌功能恢复的时间进程。 结果将为确定剂量和 激动剂在未来临床试验中的暂时性应用 唾液功能减退的患者。

DESCRIPTION (Adapted from investigator's Abstract): Salivary mucin glycoproteins help protect hard and soft surfaces of the oral cavity. Mucins are secreted in large part by mucous glands (e.g., sublingual and labial glands) which are composed primarily of mucous acinar cells. Decreased availability of mucins is linked to effects of salivary gland hypofunction (i.e., increased dental caries and lack of lubrication). Current treatment for hyposalivation includes the systemic application of a muscarinic cholinergic agonist, pilocarpine, to directly stimulate remaining functional salivary secretory cells. Unfortunately, pilocarpine is nonspecific for the five different muscarinic receptor subtypes(s), which may explain multiple adverse side effects observed in clinical trials. Currently, drug companies are attempting to develop subtype specific agonists as well as targeted drug delivery systems for sustained or regulated release of a drug. Soon it may be possible to deliver, locally, a muscarinic agonist (either subtype or non-subtype selective) to augment salivary secretion in patients suffering from hyposalivation. A drug may thus be delivered in a regulated manner at a higher and more effective dose, but with reduced side effects and increased patient compliance. It is, therefore, imperative to understand how secretory cell receptors are regulated by exposure to agonist, both with respect to agonist concentration and time of exposure to provide a framework to base experimental therapeutic regimens in future clinical trials. Given the importance of mucins in protection of the oral cavity and the primary role of muscarinic receptors in eliciting mucous cell secretion, studies are proposed to determine the regulation by agonist of muscarinic receptor function and expression in salivary mucous glands. As our model system, rat sublingual glands, which are similar to many mucous glands in humans, will be used. Specifically, isolated acinar structures will be used to: a.) Determine acinar exocrine function in response to persistent agonist challenge; b.) Determine muscarinic receptor reserve in activating mucin secretion; c.) Elucidate the quantitative and temporal relationship between persistent agonist challenge and receptor sequestration and downregulation; d.) Define mechanisms responsible for agonist induced receptor downregulation; and e.) Determine the time course for recovery of receptor expression and exocrine function. Results will provide specific information for determination of the dose and temporal administration of agonist in future clinical trials to treat patients with salivary hypofunction.