Molecular mechanisms of ammonia metabolism

氨代谢的分子机制

• 批准号: 8397578
• 负责人: I. David Weiner
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397578
• 关键词: Acids; Address; Adult; Alkalosis; Ammonia; Cell membrane; Cells; Chronic Kidney Failure; Data; Dietary Potassium; Diffusion; Disease; Duct (organ) structure; Excretory function; Gene Deletion; Glycoproteins; Goals; Growth; HSV glycoprotein C; Health; Homeostasis; Hypokalemia; Intercalated Cell; Ion Transport; Kidney; Kidney Calculi; Lead; Lipids; Macaca mulatta; Malnutrition; Mediating; Metabolic; Metabolic acidosis; Metabolism; Modeling; Molecular; Morbidity - disease rate; Movement; Mus; Muscular Atrophy; Osteopenia; Osteoporosis; Permeability; Physiological; Potassium; Potassium Deficiency; Production; Publishing; Role; Skeletal Muscle; Solubility; Stimulus; Technology; Testing; Transgenic Mice; Veterans; base; insight; novel; public health relevance; response; urinary

DESCRIPTION (provided by applicant): A major advance in our understanding of acid-base homeostasis and ammonia metabolism is the identification that Rh glycoproteins are ammonia transporters. In the kidney, published data and our preliminary data indicates that Rh glycoprotein B Glycoprotein (Rhbg) mediates a previously unrecognized role in renal ammonia metabolism. A second advance has been the recognition that Rhbg is expressed in principal cells, a cell not generally known to be involved in acid-base homeostasis, and that adaptive changes in principal cell Rhbg may be an important component of the renal response to metabolic acidosis. Thus, the overall aim of this application is to determine Rhbg's role in acid-base homeostasis and in potassium homeostasis. The first goal is to determine the specific role of Rhbg in the renal response to metabolic acidosis. We will use Cre-loxP technology to generate transgenic mice with kidney-specific, intercalated cell-specific and principal cell-specific Rhbg deletion. We will also generate mice with kidney-specific Rhbg and Rhcg deletion. We will then examine acid-base homeostasis in these mice under control conditions and in response to metabolic acidosis in order to determine the specific role of Rhcg in renal acid-base homeostasis, and the specific contributions of intercalated cells and principal cells to acid-base homeostasis. Our second aim is to determine Rhbg's specific role in the renal response to hypokalemia. We will again use Cre-loxP technology to generate transgenic mice with kidney-specific, intercalated cell-specific and principal cell-specific Rhbg deletion. We will then examine acid-base and potassium homeostasis in these mice under control conditions and in response to dietary potassium deficiency in order to determine Rhbg's role in the renal response to hypokalemia, and the specific contributions of intercalated cells and principal cells to Rhbg-mediated ion transport in response to hypokalemia.

描述（由申请人提供）： 我们对酸碱稳态和氨代谢理解的一个重大进展是确定了 Rh 糖蛋白是氨转运蛋白。在肾脏中，已发表的数据和我们的初步数据表明，Rh 糖蛋白 B 糖蛋白 (Rhbg) 在肾氨代谢中介导先前未被认识的作用。第二个进展是认识到 Rhbg 在主细胞中表达，而这种细胞通常不参与酸碱稳态，并且主细胞 Rhbg 的适应性变化可能是酸碱平衡的重要组成部分。 肾脏对代谢性酸中毒的反应。因此，本申请的总体目标是确定 Rhbg 在酸碱稳态和钾稳态中的作用。 第一个目标是确定 Rhbg 在肾脏对代谢性酸中毒反应中的具体作用。我们将使用Cre-loxP技术来产生具有肾脏特异性、插入细胞特异性和主细胞特异性Rhbg缺失的转基因小鼠。我们还将生成具有肾脏特异性 Rhbg 和 Rhcg 缺失的小鼠。然后，我们将在对照条件下检查这些小鼠的酸碱稳态，并响应代谢性酸中毒，以确定 Rhcg 在肾脏酸碱稳态中的具体作用，以及嵌入细胞和主细胞对酸碱的具体贡献体内平衡。 我们的第二个目标是确定 Rhbg 在肾脏对低钾血症反应中的具体作用。我们将再次使用Cre-loxP技术来产生具有肾脏特异性、插入细胞特异性和主细胞特异性Rhbg缺失的转基因小鼠。然后，我们将检查这些小鼠在对照条件下和对饮食缺钾的反应中的酸碱和钾稳态，以确定 Rhbg 在肾脏对低钾血症反应中的作用，以及嵌入细胞和主细胞对 Rhbg 介导的特定贡献响应低钾血症的离子转运。