THEORY OF SOLUTE AND WATER TRANSPORT ACROSS EPITHELIA

哺乳动物集合管的数学模型将是 已开发，由皮质、外髓质细胞模型组成 和内髓节段。该模型将代表Na+，K+， 以及在正常和病理条件下的酸/碱运输， 并将预测他们的肾脏排泄量，考虑到远端分娩。这个 最初的关注点将是正常收集风管的参数指定 在功能和荷尔蒙刺激期间。重要的裁员 已在电解质运输途径中发现：鲁米那 Na~+共转运或Na~+通道的膜Na~+通量 通过H+-ATPase或H+，K+-ATPase分泌；肾小管周围碱基出口 通过C；-/HCO3-交换或NH4+-NH3循环。 这项调查将估计这些通量成分，并确定 可以毫不含糊地使用的实验动作 确认这些估计。我们将特别关注手机 容量调节，特别是在内髓集合管， 它可以改变它的钠离子转运速度，从快速重吸收到 分泌物，并面临很大范围的管腔液体的色调。 动态平衡控制机制强调了离子的调节 通道活动：管腔膜钠通道和小管周 膜上K+和C_1-通道。模型模拟将检验 这些拟议机制的可行性，在暂时性和非暂时性 稳态环境扰动。，第二个焦点将是 集合管功能障碍的模拟。在实验模型中 (输尿管梗阻，阿米洛利或锂)，特殊 已发现节段性运输缺陷。该模型将 评估已知缺陷的充分性以使观察到的溶质合理化 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，经肾小管K+梯度，影响 利尿剂和阴离子对尿液pH值的影响)。这样的测试已经 传统上被用来推断患者的特定运输缺陷 伴有K+代谢紊乱或尿酸。这 将通过规划特定的运输来仔细检查方法 缺陷，对模型进行模拟测试，并评估 推断缺陷的能力。

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.