Theory of Solute and Water Transport Across Epithelia

描述(由申请人提供)：本项目的总体目标是对肾小管内液体和电解质紊乱进行数学建模和计算机模拟。到目前为止，这个项目已经建立了近端曲小管的模型，以及远端曲小管通过皮质、外髓和内髓收集管的所有节段。在下一个研究阶段，第一个目标是将粗大的升支Henle肢(AHL)模拟为孤立的小管，并在远端肾单位功能的背景下进行模拟。远端肾单位模型将被用来检验延髓间质钾浓度可以通过调节钠向远端小管和集合管的输送来控制肾脏整体钾和酸排泄的提议。酸碱平衡紊乱可能源于AHL功能异常。具体地说，伴有高钾血症的AHL功能下降与低醛固酮血症的铵排泄障碍有关。AHL功能降低也是巴特综合征的主要特征，这是一种与代谢性碱中毒相关的疾病。模型将被用来表征在每种条件下对酸排泄的节段性贡献。第二个目标是将所有节段性模型(增加近端直管和细小的Henle肢体)整合成完整的肾单位。最初，这些问题将根据规定的间质成分解决，以检查节段之间的管腔相互作用，但最终必须解决间质变量，以模拟肾小管周围环境的肾小管改变。主要的代谢紊乱，如高钾血症和酸中毒，已被证明会改变肾脏髓质的溶质，从而影响尿液成分；这将是模拟这种影响的第一次尝试。第三个目标是将控制理论应用于AHL模型，以确定负责细胞内稳态的调控转运蛋白，具体地说，是用于在保持细胞体积和pH的同时调节大量钠和铵的再吸收通量的机制。遗传性电解质代谢障碍或药物干预通常会影响单个肾小管中的单个转运体。然而，对整体肾功能的影响可能是深远的，影响到其他节段，无论是相邻的还是相距较远的。这样的模型可以解释由于分子缺陷而导致的整个器官功能障碍的模式。

DESCRIPTION (provided by applicant): The overall objective of this project is mathematical modeling and computer simulation of fluid and electrolyte disorders in kidney tubules. To date, this project has formulated models of proximal convoluted tubule, and all segments from distal convoluted tubule through cortical, outer medullary, and inner medullary collecting ducts. In the next investigational period, the first objective is to model the thick ascending Henle limb (AHL), both as an isolated tubule, and within the context of distal nephron function. The distal nephron model will be used to examine the proposal that medullary interstitial potassium concentration may control overall renal potassium and acid excretion, by modulating sodium delivery to distal tubule and collecting duct. Disorders of acid/base balance may derive from abnormal AHL function. Specifically, decreased AHL function with hyperkalemia has been implicated in the impaired ammonium excretion of hypoaldosteronism. Decreased AHL function is also the key feature of Bartter's syndrome, a disorder associated with metabolic alkalosis. Models will be used to characterize segmental contributions to acid excretion in each of these conditions. The second objective is to integrate all of the segmental models (adding proximal straight tubule and thin Henle limbs) into full nephrons. Initially, these will be solved against a prescribed interstitial composition, to examine luminal interactions among the segments, but ultimately interstitial variables must be solved in order to simulate tubular modification of the peritubular environment. Major metabolic derangements, such as hyperkalemia and acidosis, have been shown to alter renal medullary solutes and thus influence urine composition; this will be the first effort to simulate that impact. The third objective will be the application of control theory to the AHL model, in order to identify 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. Genetic disorders of electrolyte metabolism or pharmacologic intervention will generally affect a single transporter in a single kidney tubule. However, the impact on overall kidney function may be far-reaching, affecting other segments, both adjacent and at a distance. Models such as these can explain the pattern of whole-organ malfunction as the consequence of a molecular defect.