Intestinal Epithelia Ammonium Transport

描述(申请人提供)：一些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。结肠中的离子传输一直是人们特别感兴趣的目标。人们很早就认识到，结肠流出物中的氨(NH4)远远超过全身NH4浓度，在肝功能衰竭的情况下，全身NH4水平可能超过中毒浓度。虽然结肠对NH4的吸收被广泛认识，但在结肠中调节氨(NH3)/NH4运输的可能性几乎没有受到关注，尽管这种运输确实发生在暴露在高NH4环境中的一些上皮细胞中。此外，结肠腔内相对较高和可变的NH4对离子和液体平衡运输的影响还知之甚少。这一建议将涉及：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；2)非重组人G介导的NH3/NH4在结肠中分泌转运的机制；3)NH3/NH4分泌的调节。本项目将主要关注NH3/NH4在结肠内的转运机制，使用结肠细胞系T84和小鼠远端结肠作为模型。在各种条件下，可以通过单向通量分析获得NH3/NH4的载体转运。NH4转运机制的生理重要性以及与已知的肾脏和鱼的鳃转运机制的相似性将通过小鼠结肠获得。目前，尽管门静脉NH4浓度在肝病高氨血症发生发展中的作用是众所周知的，但肠道NH3/NH4转运的机制还不是很清楚，也知之甚少。更好地了解NH4的转运机制和调节机制，对于开发更有效的治疗分泌失调和肝脏相关性高氨血症的方法具有重要的潜力。与公共卫生相关：血氨水平升高会导致大脑功能障碍，被称为高氨血症引起的脑病，如果不治疗，可能会危及生命。肝脏疾病通常是高氨血症的原因，然而，目前可能有不适或严重副作用的治疗方案针对肠道，以努力将氨吸收降至最低。该项目的长期目标是改进对高氨血症的治疗。

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.