Physiology of Mucus-Secreting Salivary Glands

数以百万计的美国人的生活质量受到各种病因引起的唾液腺功能减退的不利影响，包括全身性疾病、放射治疗、干性药物和Sj6gren综合征。干预措施的发展，以恢复这些人的功能需要一个彻底的了解唾液腺的分子生理学。唾液分泌包括两步过程：腺泡细胞最初分泌等渗浆样液体；导管细胞随后修改这种初级分泌以保存NaC1。液体分泌和NaC1重吸收过程都依赖于多种Na+转运机制的协同作用，包括Na+/H+交换体、Na+通道和Na+/K+/2C1-共转运体。转基因小鼠已被证明是人类唾液腺功能障碍的有价值的模型，并有助于确认重要的Na+转运体的分子特性和功能特性。然而，我们对主要的Na+转运蛋白的功能的理解仍有很大的差距。为了解决剩下的问题，我们提出了人类和小鼠唾液腺中Na+转运体生理学的分子和功能比较。我们将测试Na+转运蛋白对唾液形成至关重要的整体假设。具体而言：Aim 1)将利用靶向破坏Na+通道ENaC （Scrmla）和Na+/H+交换器Nhe4 [Slc9a4]基因产生的转基因小鼠，直接测试这些Na+转运蛋白是否对唾液腺分泌至关重要；目的2)将评估动员细胞内ca2 +或增加细胞内cAMP含量的激动剂是否会急性调节人类和小鼠唾液细胞中不同Na+转运机制的活性；和Aim 8)将确定基因破坏是否通过系统性或腺体特异性机制影响唾液的产生。最终，从这些目标中获得的信息将有助于开发治疗各种形式的唾液腺功能障碍的疗法。

DESCRIPTION: The quality of life for millions of Americans is adversely affected by salivary gland hypofunction caused by a variety of etiologies including systemic diseases, radiation therapy, xerogenic medications, and Sj6gren's syndrome. The development of interventions to restore function for these individuals requires a thorough understanding of the molecular physiology of salivary glands. Salivary secretion involves a two-step process: acinar cells initially secrete an isotonic, plasma-like fluid; duct cells subsequently modify this primary secretion to conserve NaC1. Both the fluid secretion and NaC1 reabsorption processes are dependent upon the coordinated action of multiple Na+ transport mechanisms including Na+/H+ exchangers, Na+ channels, and Na+/K+/2C1- co-transporters. Genetically modified mice have proven to be valuable models of human salivary gland dysfunction, and are useful for confirming the molecular identities and the functional properties of important Na+ transporters. Nevertheless, significant gaps remain in our understanding of the function of the major Na+ transporting proteins. To address remaining questions, we propose a molecular and functional comparison of Na+ transporter physiology in human and mouse salivary glands. We will test the overall hypothesis that Na+ transport proteins are critical to saliva formation. Specifically: Aim 1) will take advantage of genetically modified mice generated by targeted disruption of the Na+ channel ENaC (Scrmla) and the Na+/H+ exchanger Nhe4 [Slc9a4) genes to directly test whether these Na+ transport proteins are essential for salivary gland secretion; Aim 2) will assess whether agonists that mobilize intracellular Ca 2+, or increase the intracellular cAMP content, acutely regulate the activity of the different Na+ transport mechanisms in human and mouse salivary cells; and Aim 8) will determine whether gene disruption affects saliva production through systemic or gland-specific mechanisms. Ultimately, the information gained from these Aims will aid in the development of therapies to remedy various forms of salivary gland dysfunction.