REGULATION OF GLANDULAR MUCOUS CELL SECRETION

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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.