REGULATION OF GLANDULAR MUCOUS CELL SECRETION

描述（改编自研究者摘要）：唾液粘蛋白 糖蛋白有助于保护口腔的硬表面和软表面。 粘蛋白大部分由粘液腺分泌（例如，舌下和 唇腺），其主要由粘液腺泡细胞组成。 粘蛋白的可用性降低与唾液腺的影响有关 功能减退（即，增加龋齿和缺乏润滑）。 目前对唾液分泌不足的治疗包括全身应用 毒蕈碱胆碱能激动剂，毛果芸香碱，直接刺激剩余的 功能性唾液分泌细胞 不幸的是毛果芸香碱 对五种不同的毒蕈碱受体亚型是非特异性的， 可以解释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亚型特异性 激动剂以及用于持续或 药物的调节释放。 很快，就有可能在当地提供一个 毒蕈碱激动剂（亚型或非亚型选择性）， 唾液分泌不足患者的唾液分泌。 药物可以 从而以更高和更有效的剂量以调节的方式递送， 但副作用减少且患者依从性增加。 是的， 因此，必须了解分泌细胞受体是如何 受激动剂暴露的调节，无论是在激动剂浓度方面 和暴露时间，以提供一个框架， 在未来的临床试验中。 考虑到粘蛋白在 保护口腔和毒蕈碱受体的主要作用 在引起粘液细胞分泌方面，建议进行研究以确定 毒蕈碱受体功能和表达的激动剂调节， 唾液粘液腺 作为我们的模型系统，大鼠舌下腺， 类似于人类的许多粘液腺，将被使用。 具体地说， 分离的腺泡结构将用于：a.）确定腺泡外分泌 响应于持续激动剂攻击的功能; B.）确定 激活粘蛋白分泌的毒蕈碱受体储备; c.）阐明 持续激动剂激发之间的定量和时间关系 和受体螯合和下调; d.）界定机制 负责激动剂诱导的受体下调;和e.）确定 受体表达和外分泌功能恢复的时间过程。 结果将为确定剂量提供具体信息， 在未来临床试验中暂时给予激动剂以治疗 唾液腺功能减退的患者。

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.