Intestinal Epithelia Ammonium Transport

肠上皮铵转运

• 批准号: 8009562
• 负责人: ROGER T WORRELL
• 金额: $ 1.65万
• 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: 2010-01-07 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009562
• 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液体运输失调，导致腹泻或便秘。在过去的50年里，大量的研究集中在这些异常的可能机制和治疗上。离子在结肠中的运输一直是一个特别感兴趣的目标。人们很早就认识到，结肠流出物中的铵（NH4+）远远超过全身铵（NH4+）浓度，在肝功能衰竭的情况下，全身铵（NH4+）水平可能超过毒性浓度。虽然人们普遍认为结肠对NH4+的吸收，但在结肠中调节氨(NH3) / NH4+运输的可能性却很少受到关注，尽管这种运输确实发生在暴露于高NH4+环境的许多上皮中。此外，人们对结肠内相对高且多变的NH4+对离子平衡和流体输送的影响知之甚少。本课题将研究：1)恒河猴相关糖蛋白NH4+转运体在结肠中的表达模式和功能作用，2)非rhg介导的NH3/NH4+在结肠中的分泌运输机制，3)NH3/NH4+分泌的调控。本项目将主要以结肠细胞系、T84和小鼠远端结肠为模型，研究NH3/NH4+在结肠内的转运机制。载体NH3/NH4+运输将通过单向通量测定在各种条件下获得。通过小鼠结肠，我们将了解NH4+转运机制的生理重要性及其与已知肾和鱼鳃转运机制的相似性。尽管众所周知门静脉NH4+浓度在肝病高氨血症发生中的作用，但目前肠道NH3/NH4+转运的机制尚不明确，也不清楚。更好地了解NH4+的转运机制和调控将对开发更有效的治疗分泌失调和肝相关性高氨血症具有重要的潜力。公共卫生相关性：血氨水平升高可引起脑功能障碍，即高氨血症引起的脑病，如果不及时治疗，可能会危及生命。肝脏疾病通常是高氨血症的原因，然而目前的治疗方案可能有不舒服或严重的副作用是针对肠道，以尽量减少氨的吸收。该项目的长期目标是为高氨血症提供更好的治疗方法。