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: 6370103
• 负责人: ALAN M WEINSTEIN
• 金额: $ 24.39万
• 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/6370103
• 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.

哺乳动物远端肾单位的数学模型将被开发，包括上行汉勒肢，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/碱转运，并将预测远端递送的肾排泄。 该项目从三个集合管段的模型开始;它需要开发两个远端小管段加上一个升支，然后将所有段连接成一个远端肾单位。 节段模型将纳入特定膜转运蛋白的表示：远端小管中的Na-CI协同转运蛋白，以及升支中的腔Na-K-2CI和管周K-CI协同转运蛋白。 将考虑具体部门的问题以及部门间的相互作用。 对于集合管，将检查远端肾小管酸中毒（ATP酶衰竭、基底出口缺陷或细胞旁渗漏）的潜在病变，并模拟识别这些病变的临床试验。 本研究的目的是探讨远端肾小管性酸中毒临床分类的合理性。 远端小管模型将用于检查钾分泌的流量依赖性，以估计可归因于管腔梯度衰减的组分。 这将是初步量化的碱化和钾浪费作用的噻嗪类利尿剂，这对远端小管。 在升支，一个重要的重点将是确定调制的转运负责细胞内稳态，特别是，用于容纳大的钠和铵的重吸收通量，同时保持细胞体积和pH值的机制。在升支，三种不同的运输缺陷，都存在巴特综合征将被模拟，了解钾缺乏症常见的所有三个。完整的远端肾单位模型将被要求严格审查的建议，髓质间质钾浓度调节整体肾钾和酸排泄：即通过钝化升支钠重吸收，管周钾发送更多的钠到远端小管和集合管，钾分泌和碱重吸收取决于钠的输送。