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肾小管液体和电解质紊乱的数学建模和计算机模拟。迄今为止，本项目已建立了近曲小管模型，以及从远曲小管到皮质、外髓和内髓集合管的所有节段模型。在下一个研究阶段，第一个目标是建立一个单独的肾小管和远端肾单位功能的模型。远端肾单位模型将用于检查以下提议：髓质间质钾浓度可通过调节钠向远端小管和集合管的递送来控制总体肾钾和酸排泄。酸/碱平衡紊乱可能源于阿勒功能异常。具体而言，阿勒功能降低伴高钾血症与醛固酮减少症的氨排泄受损有关。阿勒功能下降也是巴特综合征（一种与代谢性碱中毒相关的疾病）的关键特征。模型将用于表征在这些条件下对酸排泄的节段性贡献。第二个目标是将所有节段模型（添加近端直小管和细Henle肢）整合到完整的肾单位中。最初，这些将被解决对规定的间质组成，以检查管腔之间的相互作用的部分，但最终间质变量必须解决，以模拟肾小管周围环境的肾小管修改。主要的代谢紊乱，如高钾血症和酸中毒，已被证明会改变肾髓质溶质，从而影响尿液成分;这将是第一次尝试模拟这种影响。第三个目标将是应用控制理论的阿勒模型，以确定负责细胞内稳态的调制的转运蛋白，具体地说，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。遗传性疾病的电解质代谢或药理学干预通常会影响一个单一的转运蛋白在一个单一的肾小管。然而，对整体肾功能的影响可能是深远的，影响到邻近和远处的其他节段。像这样的模型可以解释整个器官功能障碍的模式是分子缺陷的结果。

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.