Intestinal Epithelia Ammonium Transport

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转运失调，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方法上。结肠中的离子转运一直是特别感兴趣的目标。早期认识到结肠流出物中的铵（NH 4+）远远超过全身NH 4+浓度，并且在肝衰竭的情况下，全身NH 4+水平可能超过毒性浓度。虽然NH 4+的结肠吸收被广泛认可，但结肠中调节氨（NH3）/NH 4+转运的可能性很少受到关注，尽管这种转运确实发生在暴露于高NH 4+环境的许多上皮细胞中。此外，相对较高的和可变的NH 4+在结肠腔中的平衡离子和流体运输的影响知之甚少。该提案将涉及：1）恒河猴相关糖蛋白NH 4+转运蛋白沿着结肠的表达模式和功能作用; 2）结肠NH3 /NH 4+分泌转运的非RhG介导机制; 3）NH3/NH 4+分泌的调节。本项目主要以结肠细胞系T84和小鼠远端结肠为模型，研究NH3/NH 4+在结肠内的转运机制。将在各种条件下通过单向通量测定法获得矢量NH3/NH 4+转运。NH 4+转运机制的生理重要性以及与已知的肾和鱼鳃转运机制的相似性将使用小鼠结肠进行评估。目前，肠道NH3/NH 4+转运的机制尚不清楚，也知之甚少，尽管门静脉NH 4+浓度在肝病高氨血症的发展中具有众所周知的影响。更好地了解NH 4+转运机制和调节将在更有效地治疗分泌失调和肝相关高氨血症的发展中具有重要的潜力。公共卫生相关性：血氨水平升高会导致脑功能障碍，称为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，目前可能具有不舒服或严重副作用的治疗方案针对肠道，以尽量减少氨吸收。该项目的长期目标是为高氨血症提供更好的治疗。

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.