Molecular mechanisms of ammonia metabolism

氨代谢的分子机制

• 批准号: 8198381
• 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/8198381
• 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. PUBLIC HEALTH RELEVANCE: Acid-base disorders are common in veterans, and are associated with osteoporosis, muscle atrophy, growth retardation, renal stone disease and increased morbidity. They may also contribute to the progression of chronic kidney disease. The proposed studies will provide new insights into mechanisms of acid-base homeostasis, and thereby provide the necessary underpinnings for new and novel treatments for veterans with acid-base disorders.

描述（由申请人提供）： 我们对酸碱平衡和氨代谢的理解的一个主要进展是确定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）介导了以前未被认识到的肾氨代谢的作用。第二个进展是认识到Rhbg在主细胞中表达，所述主细胞是通常不知道参与酸碱平衡的细胞，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。 肾对代谢性酸中毒的反应。因此，本申请的总体目的是确定Rhbg在酸碱平衡和钾平衡中的作用。 第一个目标是确定Rhbg在代谢性酸中毒的肾脏反应中的具体作用。我们将使用Cre-loxP技术产生具有肾脏特异性、嵌入细胞特异性和主细胞特异性Rhbg缺失的转基因小鼠。我们还将产生具有肾特异性Rhbg和Rhcg缺失的小鼠。然后，我们将检查酸碱平衡在这些小鼠在控制条件下，并在响应代谢性酸中毒，以确定具体的作用，Rhcg在肾脏酸碱平衡，和具体的贡献，闰细胞和主细胞的酸碱平衡。 我们的第二个目的是确定Rhbg在低钾血症的肾脏反应中的具体作用。我们将再次使用Cre-loxP技术来产生具有肾特异性、嵌入细胞特异性和主细胞特异性Rhbg缺失的转基因小鼠。然后，我们将检查酸碱和钾稳态在这些小鼠在控制条件下，并在饮食中钾缺乏，以确定Rhbg的作用，在肾脏对低钾血症的反应，和具体的贡献的嵌入细胞和主细胞Rhbg介导的离子转运在低钾血症。 公共卫生关系： 酸碱平衡紊乱在退伍军人中很常见，并与骨质疏松症、肌肉萎缩、生长迟缓、肾结石病和发病率增加有关。它们也可能导致慢性肾脏疾病的进展。拟议的研究将为酸碱平衡机制提供新的见解，从而为患有酸碱平衡紊乱的退伍军人的新的和新颖的治疗提供必要的基础。