THEORY OF SOLUTE AND WATER TRANSPORT ACROSS EPITHELIA

哺乳动物集合管的数学模型将是 发达国家，包括皮质，外髓细胞模型 和内髓段。 该模型将代表Na+，K+， 以及正常和病理条件下的酸/碱转运， 并将预测它们的肾脏排泄，给定远端递送。 的 初始焦点将是正常集合管的参数分配 功能和激素刺激期间。 重要的冗余 已在电解质转运途径中确定：管腔 Na+通过NaCl共转运或Na+通道的膜Na+通量 通过H+-ATP酶或H+，K+-ATP酶分泌;管周基底出口 通过C +/HCO 3-交换或通过NH 4 + -NH 3再循环。 这项研究将估计这些通量分量，并确定 这些实验性的机动动作， 符合这些估计。 将特别注意细胞 容量调节，尤其是内髓集合管， 它可以改变其钠离子转运速率， 分泌，并且其面临宽范围的腔流体张力。 稳态控制机制强调离子的调制 通道活性：管腔膜Na+通道和管周通道 膜K+和C1-通道。 模型模拟将检验 这些拟议机制的可行性，在瞬态和 稳态环境扰动，第二个重点将是 模拟集合管功能障碍。 在实验模型中 （输尿管梗阻，阿米洛利或锂给药），特异性 已经识别出分段运输缺陷。 该模型将 评估已知缺陷是否足以合理解释观察到的溶质 排泄模式 最后，该模型将模拟临床试验， 远端肾单位功能（例如经前庭K+梯度， 利尿剂和不渗透阴离子对尿pH的影响）。 这些测试有 传统上用于推断患者的特定运输缺陷 K+代谢紊乱或尿酸化。 这 将通过规划具体的运输方式来审查这种方法 缺陷，对模型进行模拟测试，并评估 能够推断出缺陷。

A mathematical model of the mammalian collecting duct will be developed, comprised of cellular models of cortical, outer medullary and inner medullary segments. The model will represent Na+, K+, and acid/base transport under normal and pathological conditions, and will predict their renal excretion, given distal delivery. The initial focus will be parameter assignment for normal collecting duct function and during hormonal stimulation. Important redundancies have been identified in electrolyte transport pathways: luminal membrane Na+ flux via NaCl cotransport or Na+ -channel; H+ secretion via H+-ATPase or H+, K+-ATPase; peritubular base exit via c;-/HCO3- exchange or by means of NH4+ - NH3 recycling. This investigation will estimate these flux components, and identify experimental maneuvers which may be used to unambiguously conform these estimates. Particular attention will be paid to cell volume regulation, especially in inner medullary collecting duct, which can vary its Na+ transport rat from brisk reabsorption to secretion, and which faces a wide range in luminal fluid tonicity. Homeostatic control mechanisms have emphasized modulation of ion channel activity: luminal membrane Na+-channel and peritubular membrane K+ and C1- channels. Model simulations will examine feasibility of these proposed mechanisms, under both transient and steady state environmental perturbations., The second focus will be simulation of collecting duct dysfunction. In experimental models (ureteral obstruction, amiloride or lithium administration), specific segmental transport defects have been identified. The model will assess the adequacy of known defects to rationalize observed solute excretion patterns. Finally, the model will simulate clinical tests of distal nephron function (e.g. transtubular K+ gradient, impact of diuretics and impermeant anions on urinary pH). Such tests have traditionally been used to infer specific transport defects in patients with disorders of K+ metabolism or urinary acidification. This approach will be scrutinized by programming specific transport defects, subjecting the model to simulated testing, and assessing the ability to infer the defect.