Theory of Solute and Water Transport Across Epithelia

项目描述（由申请人提供）：本项目的总体目标是对肾小管中的液体和电解质紊乱进行数学建模和计算机模拟。迄今为止，本项目已经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，第一个目标是建立厚的上行亨勒肢（AHL）模型，既作为一个孤立的小管，也在远端肾元功能的背景下。远端肾元模型将用于检验髓质间质钾浓度可能通过调节钠向远端小管和集管的输送来控制肾脏钾和酸的排泄。酸碱平衡失调可能源于AHL功能异常。具体来说，高钾血症导致AHL功能下降与低醛固酮增多症导致的铵排泄受损有关。AHL功能下降也是Bartter综合征（一种与代谢性碱中毒相关的疾病）的主要特征。模型将用于描述在每种情况下对酸排泄的部分贡献。第二个目标是将所有节段模型（添加近端直小管和薄Henle肢）整合到完整的肾元中。最初，这些将根据规定的间隙成分来解决，以检查节段之间的管腔相互作用，但最终必须解决间隙变量，以模拟小管周围环境的小管修饰。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；这将是模拟这种影响的第一次努力。第三个目标是将控制理论应用于AHL模型，以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。电解质代谢的遗传疾病或药物干预通常会影响单个肾小管中的单个转运蛋白。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。诸如此类的模型可以解释由分子缺陷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.