H/HCO3 transport in the collecting duct

描述（由申请人提供）：我们对关键肾功能的理解的一个重大进展是最近认识到谷氨酰胺合成酶可能介导肾电解质和氮代谢中的关键作用。谷氨酰胺合成酶介导NH 4+和谷氨酸转化为谷氨酰胺，从而“不生成”氨并“再生”有用的氨基酸谷氨酰胺。谷氨酰胺合成酶在肾脏的多种不同细胞类型中表达，包括参与氨生成的细胞（近端小管） 以及传统上认为仅参与氨转运的细胞（插入细胞）。谷氨酰胺合成酶在这些细胞类型中的存在，以及我们在多种条件下确定其调节的初步数据表明调节肾氨代谢和调节氮平衡的新机制。 本申请的总体目的是确定谷氨酰胺合成酶在肾脏中不同主要细胞类型中的作用，其中谷氨酰胺合成酶在肾氨、酸碱、钾和氮代谢中表达。 第一个目标是确定谷氨酰胺合成酶在近曲小管中表达的具体作用。我们将使用Cre-loxP技术产生近端小管特异性谷氨酰胺合成酶缺失的小鼠，我们将使用该技术来确定近端小管谷氨酰胺合成酶在正常酸碱平衡中的作用，以及在对代谢性酸中毒、低钾血症和饮食蛋白限制的肾脏反应中的作用。 我们的第二个目的是确定谷氨酰胺合成酶在闰细胞中表达的具体作用。我们将使用Cre-loxP技术来产生具有嵌入细胞特异性谷氨酰胺合成酶缺失的小鼠。我们将使用这些小鼠来确定嵌入细胞谷氨酰胺合成酶在正常酸碱平衡中的作用，以及在肾脏对代谢性酸中毒、低钾血症和饮食蛋白限制的反应中的作用。

DESCRIPTION (provided by applicant): A major advance in our understanding of key renal function is the recent recognition that the enzyme glutamine synthetase may mediate critical roles in renal electrolyte and nitrogen metabolism. Glutamine synthetase mediates the conversion of NH4+ and glutamate into glutamine, thereby "ungenerating" ammonia and "regenerating" the useful amino acid glutamine. Glutamine synthetase is expressed in multiple distinct cell types in the kidney, including cells involved in ammonia generation (proximal tubule) and those traditionally thought to be involved solely in ammonia transport (intercalated cells). The presence of glutamine synthetase in these cell types, and our preliminary data identifying its regulation in multiple conditions suggests novel and new mechanisms regulating renal ammonia metabolism and in the regulation of nitrogen balance. The overall aim of this application is to determine the roles of glutamine synthetase in the different major cell types in the kidney in which it is expressed in renal ammonia, acid-base, potassium and nitrogen metabolism. The first goal is to determine the specific role of glutamine synthetase expression in the proximal tubule. We will use Cre-loxP technology to generate mice with proximal tubule-specific glutamine synthetase deletion, which we will use to determine the role of proximal tubule glutamine synthetase in normal acid-base homeostasis, and in the renal response to metabolic acidosis, hypokalemia and dietary protein restriction. Our second aim is to determine the specific role of glutamine synthetase expression in intercalated cells. We will use Cre-loxP technology to generate mice with intercalated cell-specific glutamine synthetase deletion. We will use these mice to determine the role of intercalated cell glutamine synthetase in normal acid- base homeostasis, and in the renal response to metabolic acidosis, hypokalemia and dietary protein restriction.