Intestinal Epithelia Ammonium Transport

肠上皮铵转运

• 批准号: 8013471
• 负责人: ROGER T WORRELL
• 金额: $ 1.89万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-20 至 2012-02-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013471
• 关键词: ATP phosphohydrolase; Acids; Address; Adverse effects; Affect; Agonist; Ammonia; Ammonium; Apical; Attention; Biological Assay; Biological Models; Blood; Blood Circulation; Brain; Cell Line; Cells; Colon; Constipation; Cyclic AMP; Data; Development; Diarrhea; Dietary Proteins; Digestive System Disorders; Disease; Distal; Duct (organ) structure; Encephalopathies; Enterocytes; Environment; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Exposure to; Family; Fishes; Gases; Gastrointestinal tract structure; Genus Cola; Gills; Glycoproteins; Goals; Helicobacter Infections; Hepatic; Hepatic Encephalopathy; Heterogeneity; Human; Hyperammonemia; In Situ Hybridization; Intestines; Ion Transport; Ions; Kidney; Knowledge; Learning; Left; Length; Life; Liquid substance; Literature; Liver Failure; Liver diseases; Macaca mulatta; Measurement; Measures; Mediating; Membrane; Methylamines; Modeling; Molecular; Mus; NHE2; Na(+)-K(+)-Exchanging ATPase; Nephrons; Organ; Pathogenesis; Pathway interactions; Pattern; Permeability; Physiological; Portal vein structure; Process; Regulation; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Role; Route; Surface; Time; Tissues; Transgenic Mice; Up-Regulation; Villus; absorption; apical membrane; base; cell type; colonic crypt; crypt cell; gastrointestinal epithelium; improved; inhibitor/antagonist; insight; interest; intestinal epithelium; laser capture microdissection; methylamine; pH gradient; public health relevance; uptake

DESCRIPTION (provided by applicant): A number of diseases affecting the gastrointestinal tract are characterized by the dysregulation of ion and fluid transport resulting in diarrhea or constipation. Over the past fifty years, a plethora of studies have focused on possible mechanisms and treatments for these abnormalities. Ion transport in the colon has been a target of particular interest. It was recognized early on that ammonium (NH4+) in colonic effluent far exceeded that of systemic NH4+ concentration and that, in cases of liver failure, systemic NH4+ levels could exceed toxic concentrations. Although colonic absorption of NH4+ is widely recognized, the possibility of regulated ammonia (NH3) / NH4+ transport in the colon has received little attention, this despite the fact that such transport does occur in a number of epithelia exposed to a high NH4+ environment. Moreover, the effects of relative high and variable NH4+ in the colonic lumen on the balance ion and fluid transport are poorly understood. This proposal will address: 1) Expression pattern and functional role of Rhesus Associated Glycoprotein NH4+ transporters along the colon, 2) The non-RhG mediated mechanisms of secretory transport of NH3 / NH4+ in the colon, 3) Regulation of NH3/NH4+ secretion. This project will focus primarily on NH3/NH4+ transport mechanisms within the colon using the colonic cell line, T84 and mouse distal colon as models. Vectorial NH3/NH4+ transport will be accessed by unidirectional flux assay under a variety of conditions. The physiological importance of NH4+ transport mechanisms and similarity to known renal and fish gill transport mechanisms will be accessed using mouse colon. At present the mechanisms of intestinal NH3/NH4+ transport are ill defined and poorly understood, this despite the well known impact of portal vein NH4+ concentration in the development of hyperammonemia in liver disease. A better understanding of NH4+ transport mechanisms and regulation will be of significant potential in the development of more efficient treatments of secretory dysregulation and hepatic associated hyperammonemia. PUBLIC HEALTH RELEVANCE: Increased levels of blood ammonia can cause brain malfunction, referred to as hyperammonemia induced encephalopathy which if left untreated can become life threatening. Liver disease is often the cause of hyperammonemia, however current treatment regimes which may have uncomfortable or severe side effects are targeted to the intestine in an effort to minimize ammonia absorption. The long term goal of this project is to provide improved treatment for hyperammonemia.

描述（由申请人提供）：许多影响胃肠道的疾病的特征是离子和流体转运的失调导致腹泻或便秘。在过去的五十年中，大量的研究集中于这些异常的可能机制和治疗方法。结肠中的离子运输一直是特别感兴趣的目标。在结肠废水中的铵（NH4+）很早就被认识到远远超过全身性NH4+浓度的铵，并且在肝衰竭的情况下，全身NH4+水平可能会超过毒性浓度。尽管NH4+的结肠吸收被广泛认可，但结肠中调节氨（NH3） / NH4+转运的可能性很少受到关注，尽管事实确实发生了许多暴露于高NH4+环境的上皮。此外，对结肠管腔中相对高和可变的NH4+对平衡离子和液体转运的影响很少。该提案将解决：1）恒河猴相关的糖蛋白NH4+转运蛋白沿结肠的表达模式和功能作用，2）在结肠中NH3 / NH4+分泌转运的非RHG介导机制，3）调节NH3 / NH4+分泌。该项目将主要关注结肠细胞系，T84和小鼠远端结肠作为模型的结肠内NH3/NH4+传输机制。在各种条件下，将通过单向通量测定法访问矢量NH3/NH4+运输。 NH4+传输机制的生理重要性以及与已知的肾脏和鱼g传输机制的相似性将使用小鼠结肠访问。目前，肠道NH3/NH4+转运的机制尚未定义和理解不足，尽管门静脉NH4+浓度在肝病中的高氨血症发展中产生了众所周知的影响。对NH4+运输机制和调节的更好理解将在开发更有效的分泌失调和肝相关的高症中的更有效治疗方面具有重要潜力。公共卫生相关性：增加的血液氨水会引起脑功能故障，被称为高症诱导的脑病，如果不复及的话，这种脑病可能会危及生命。肝病通常是高症血症的原因，但是目前可能具有不舒服或严重副作用的治疗方案是针对肠道的，以最大程度地减少氨的吸收。该项目的长期目标是为高症血症提供改进的治疗方法。