Theory of Solute and Water Transport Across Epithelia

建立哺乳动物远端肾元的数学模型，包括上行亨勒肢、远端肾小管和收集管的细胞模型。该模型将代表正常和病理条件下钠、钾和酸/碱的转运，并预测远端分娩的肾脏排泄。项目从三个集风管段的模型开始；它需要发育两个远端小管段和一个上升肢，然后将所有段连接成远端肾元。节段模型将纳入特定膜转运蛋白的表征：在远端小管中，Na-CI共转运蛋白，在上升肢中，管腔Na-K-2CI和管周K-CI共转运蛋白。将考虑特定部门的问题以及部门之间的相互作用。对于收集管，将检查远端肾小管酸中毒的潜在病变（atp酶衰竭、碱基出口缺陷或细胞旁渗漏），并模拟识别这些病变的临床试验。在这方面，目的是检查合理化的临床分类远管性酸中毒。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成分。这将为定量噻嗪类利尿剂作用于远端小管的碱化和耗钾作用奠定基础。在上升肢体中，一个重要的重点将是确定负责细胞稳态的调节转运蛋白，特别是用于容纳钠和铵的大重吸收通量的机制，同时保持细胞体积和ph。在上升肢体中，将模拟三种不同的转运缺陷，它们都表现为巴特氏综合征，以了解所有三种常见的钾耗损性碱中毒。完整的远端肾元模型需要严格检验髓质间质钾浓度调节肾脏钾和酸排泄的建议：即，通过减弱上升肢钠的重吸收，小管周围的钾向远端小管和收集管输送更多的钠，在远端小管和收集管中钾的分泌和碱的重吸收依赖于钠的输送。

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.