Theory of Solute and Water Transport Across Epithelia

跨上皮细胞的溶质和水运输理论

• 批准号: 6696455
• 负责人: ALAN M WEINSTEIN
• 金额: $ 21.19万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-08-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696455
• 关键词: Bartter's syndrome; acid base balance; acidity /alkalinity; alkalosis; ammonia; biological fluid transport; diuretics; epithelium; kidney function; kidney pharmacology; mathematical model; membrane transport proteins; model design /development; potassium ion; renal tubular transport; renal tubule; renal tubule acidosis; saluresis; sodium potassium exchanging ATPase

A mathematical model of the mammalian distal nephron will be developed, comprised of cellular models of ascending Henle limb, distal tubule, and collecting duct. The model will represent sodium, potassium, and acid/base transport under normal and pathological conditions, and will predict renal excretion from distal delivery. The project begins with models of the three collecting duct segments; it will require development of two distal tubule segments plus an ascending limb, and then concatenation of all segments into a distal nephron. The segmental models will incorporate representations of specific membrane transporters: in distal tubule, the Na-CI cotransporter, and in ascending limb, the luminal Na-K-2CI and peritubular K-CI cotransporters. Segment-specific issues, as well as segmental interactions will be considered. For the collecting duct, proposed lesions underlying distal renal tubular acidosis (ATPase failure, base-exit defects, or paracellular leak) will be examined, and clinical tests for identifying these lesions will be simulated. In this, the objective is to examine the rationalization for the clinical taxonomy of distal tubular acidosis. The distal tubule model will be used to examine flow- dependence of potassium secretion, to estimate the component attributable to luminal gradient attenuation. This will be preliminary to quantifying the alkalinizing and potassium-wasting effect of thiazide diuretics, which act on distal tubule. In the ascending limb, an important focus will be identifying the modulated transporters responsible for cellular homeostasis, specifically, mechanisms used to accommodate large reabsorptive fluxes of sodium and ammonium, while preserving cell volume and pH. In ascending limb, the three different transport defects which all present as Bartter's syndrome will be simulated, to understand the potassium depletion alkalosis common to all three. The full distal nephron model will be required to critically examine the proposal that medullary interstitial potassium concentration modulates overall renal potassium and acid excretion: namely, that by blunting ascending limb sodium reabsorption, peritubular potassium sends more sodium to distal tubule and collecting duct where potassium secretion and base reabsorption depend on sodium delivery.

将建立哺乳动物远端肾单位的数学模型，包括升Henle肢、远端小管和集合管的细胞模型。该模型将代表正常和病理条件下的钠、钾和酸/碱运输，并将预测远端分娩的肾脏排泄。该项目从三个集合管节段的模型开始；它将需要两个远端小管节段加上一个上升肢，然后将所有节段串联成一个远端肾单位。节段性模型将包含特定膜转运体的表达：在远端小管，Na-CI共转运体，在上升肢，管腔Na-K-2CI和管周K-CI共转运体。将考虑特定于细分市场的问题以及细分市场的相互作用。对于集合管，将检查远端肾小管酸中毒(ATPase失效、碱基出口缺陷或细胞旁渗漏)潜在的拟议病变，并模拟用于识别这些病变的临床试验。在这方面，目的是检查远端肾小管性酸中毒临床分类的合理性。远端小管模型将被用来检查钾分泌的流量依赖性，以估计可归因于腔梯度衰减的成分。这将是量化作用于远端肾小管的噻嗪类利尿剂的碱化和钾浪费作用的基础。在上升端，一个重要的焦点将是确定负责细胞内稳态的调节转运蛋白，特别是在保持细胞体积和pH的同时，用于调节大的钠和铵再吸收通量的机制。在上肢，将模拟三种不同的运输缺陷，这些缺陷都表现为巴特综合征，以了解这三种疾病共同的钾缺乏性碱中毒。需要完整的远端肾单位模型来严格检验延髓间质钾浓度调节肾脏整体钾和酸排泄的提议：即通过钝化上肢钠重吸收，管周钾将更多的钠输送到远端小管和集合管，在那里钾的分泌和碱基的重吸收依赖于钠的输送。