Physiology of Mucus-Secreting Salivary Glands

描述：数以百万计的美国人的生活质量受到各种原因引起的唾液腺功能低下的不利影响，这些原因包括全身疾病、放射治疗、干燥症药物和干燥综合征。制定干预措施以恢复这些个体的功能需要彻底了解唾液腺的分子生理学。唾液分泌包括两个步骤：腺泡细胞最初分泌一种等渗的血浆样液体；导管细胞随后修改这一初级分泌以保存NaC1。体液分泌和NaCl重吸收过程都依赖于多种Na+转运机制的协调作用，包括Na+/H+交换器、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+转运体的分子身份和功能特性。然而，在我们对主要的Na+转运蛋白的功能的理解上仍然存在着重大的差距。为了解决剩下的问题，我们建议对人类和小鼠唾液腺的Na+转运体生理学进行分子和功能比较。我们将检验钠离子转运蛋白对唾液形成起关键作用的总体假设。具体地说：Aim 1)将利用通过靶向干扰Na+通道ENaC(Scrm1a)和Na+/H+交换器Nhe4[Slc9a4]基因而产生的转基因小鼠来直接测试这些Na+转运蛋白是否对唾液腺分泌是必需的；Aim 2)将评估动员细胞内钙或增加细胞内cAMP含量的激动剂是否尖锐地调节人和小鼠唾液细胞中不同的Na+转运机制的活性；以及Aim 8)将确定基因干扰将通过全身机制还是腺体特异性机制影响唾液产生。最终，从这些目的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.