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肾小球、近曲小管和从Henle升支、通过远端小管和集合管的所有节段的模型。在接下来的研究阶段，首要任务是完成肾脏节段模型库的建立，并设计出短期和 长环状肾单位，与间隙成分相对应。这些模型将模拟节段之间的轴向相互作用，如渗透性利尿或乙酰唑胺作用，并预测髓质K浓度对远端溶质输送的影响。通过迭代求解，该模型将 允许通过管球反馈表示远端溶质输送的稳定性。第二个目标将需要在项目期内投入大量精力，这将是 将肾单位模型从特定的间质推进到以间隙浓度为未知量的求解。该项目的这一方面对于评估血流变化和运输变化对肾小管周围条件的影响至关重要。它将经典的计算方法扩展到尿液浓缩机制，以及钾和酸碱代谢。主要的代谢紊乱，如高钾血症和酸中毒，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。第三个目标将是作为细胞膜转运蛋白的系统方法来检查细胞动态平衡。该方法将使用数学控制理论来识别转运体集合，这些转运体集合可以以协调的方式发挥作用，允许大量的再吸收通量，同时保持细胞体积和组成。就肾小管的实验检查而言，这些转运蛋白组合可能被视为“假说生成”。最后，实验合作正在进行中，以检验该项目的预测。与王彤博士继续研究血流依赖的近端小管运输，特别是我们提出的刷状边缘微绒毛是血流机械传感器的建议。与王博士一起计划了一个新的项目，以检查远端肾单位的血流依赖性运输，特别是与利尿剂给药导致的血流依赖性HCO-3再吸收有关。遗传性电解质代谢障碍或药物干预一般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隔很远的。这样的模型可以将整个器官的功能障碍归因于分子缺陷。 公共卫生相关性：该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和计算机模拟。高血压和水肿的部分原因可能是肾脏一个或多个区域对钠的过度吸收，利尿剂治疗钠滞留可能会对血液中的钾和碳酸氢盐水平产生不利影响。这一建模工作将为模拟疾病及其治疗提供一个工具。

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 glomerulus, proximal convoluted tubule, and all segments from ascending Henle limb, through distal tubule, and collecting duct. In the next investigational period, the first task is to complete the library of renal segmental models, and fashion short- and long-looped nephrons, solved against interstitial composition. These models will simulate axial interaction among segments, as in osmotic diuresis or acetazolamide action, and predict the impact of medullary K+ concentration on distal solute delivery. Solved iteratively, this model will allow representation of the stabilization of distal solute delivery via tubuloglomerular feedback. The second aim will require the major investment of effort for the project period, and this will be to advance the nephron models from a specified interstitium to solving for interstitial concentrations as unknown variables. This aspect of the project is critical to estimating the impact of changing flows and changing transport on peritubular conditions. It extends the classical computational approach to the urine concentrating mechanism, to K+ and acid-base metabolism. Major metabolic derangements, such as hyperkalemia and acidosis, alter renal medullary solutes and thus influence urine composition; this will be the first effort to simulate that impact. The third aim will be to examine cellular homeostasis as a systems approach to cell membrane transporters. The approach will use mathematical control theory to identify transporter ensembles, which can function in a coordinated way to allow large re-absorptive fluxes, while preserving cell volume and composition. These transporter ensembles maybe viewed as "hypothesis generation" with respect to experimental examination of kidney tubules. Finally, experimental collaborations are in progress to examine predictions from this project. Work continues with Dr. Tong Wang to examine flow-dependent proximal tubule transport, specifically our proposal that brush border microvilli are flow mechanosensors. Anew project is planned with Dr. Wang to examine flow-dependent transport in distal nephron, specifically in relation to flow-dependent HCO-3 re-absorption as a consequence of diuretic ad- ministration. Genetic disorders of electrolyte metabolism or pharmacologic intervention general- ly affect a single transporter in a single kidney tubule. However, the impact on overall kidney function maybe far-reaching, affecting other segments, both adjacent and at a distance. Such models can rationalize whole-organ malfunction as the consequence of a molecular defect. PUBLIC HEALTH RELEVANCE: The overall objective of this project is mathematical and computer modeling of fluid and electrolyte disorders in kidney tubules. Hypertension and edema maybe due in part to excessive sodium absorption in one or more regions of the kidney, and treatment of sodium retention with diuretics can have adverse effects on blood levels of potassium and bicarbonate. This modeling effort will provide a tool for simulation of both the disorders and their treatment.