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的理解的重大进步是Rh糖蛋白是氨转运蛋白的鉴定。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）介导了先前未识别的肾氨代谢作用。第二个进步是认识到RHBG在主要细胞中表达，该细胞通常不涉及酸碱稳态，并且主细胞RHBG的适应性变化可能是该细胞的重要组成部分。 肾脏对代谢性酸中毒的反应。因此，该应用的总体目的是确定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的反应中的特定作用。我们将使用CRE-LoxP技术来生成具有肾脏特异性，插入细胞特异性和主要细胞特异性RHBG缺失的转基因小鼠。我们还将用肾脏特异性RHBG和RHCG缺失产生小鼠。然后，我们将在对照条件下检查这些小鼠的酸碱稳态和对代谢性酸中毒的响应，以确定RHCG在肾酸碱稳态中的特定作用，以及插盐的细胞和主要细胞对酸碱稳态的特定贡献。 我们的第二个目的是确定RHBG在肾脏对低钾血症的反应中的特定作用。我们将再次使用CRE-LoxP技术来生成具有肾脏特异性，插入细胞特异性和主要细胞特异性RHBG缺失的转基因小鼠。然后，我们将在对照条件下检查这些小鼠的酸碱和钾稳态，并响应饮食中的钾缺乏症，以确定RHBG在肾脏对低钾血症的肾脏反应中的作用，以及介导的细胞和主要细胞对RHBG介导的离子介导的离子转运的特异性贡献，该离子介导的离子转运对低血压症的反应。