Physiology of Mucus-Secreting Salivary Glands

产品说明：数百万美国人的生活质量受到唾液腺功能减退的不利影响，唾液腺功能减退是由多种病因引起的，包括全身性疾病、放射治疗、致干燥药物和干燥综合征。发展干预措施，以恢复这些人的功能，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：腺泡细胞最初分泌等渗的血浆样液体;导管细胞随后修改这种初级分泌以保存NaCl。液体分泌和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+交换体、Na+通道和Na+/K+/2C 1-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，并用于确认重要的Na+转运蛋白的分子身份和功能特性。然而，我们对主要Na+转运蛋白功能的理解仍存在重大差距。为了解决剩下的问题，我们提出了一个分子和功能比较Na+转运生理在人类和小鼠唾液腺。我们将测试的整体假设，Na+转运蛋白是至关重要的唾液形成。具体而言：目的1）利用通过靶向破坏Na+通道ENaC（Scrmla）和Na+/H+交换器Nhe 4（Slc 9a 4）基因产生的遗传修饰小鼠，直接测试这些Na+转运蛋白是否是唾液腺分泌所必需的;目的2）研究激动剂是否能动员细胞内Ca 2+，或增加细胞内cAMP含量，急性调节人类和小鼠唾液细胞中不同Na+转运机制的活性;目标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.