THEORETICAL ANALYSIS OF SOLUTE & WATER TRANSPORT IN MAMMALIAN KIDNEYS

溶质的理论分析

• 批准号: 6122002
• 负责人: JOHN STEPHENSON
• 金额: $ 2.43万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6122002
• 关键词: biological products; biomedical resource; computers; proteins; technology /technique

The overall goal of this work is to synthesize experimental data at the membrane and molelcular level into predictive mathematical models of the mammalian kidney that are useful in understanding both its normal and diseased function. The mammalian kidney consists of a large number of units, the nephrons, operating in parallel. Each nephron is a tube approximately 1 cm long and 10 to the -3 power cm in diameter. The closed end is wrapped around a specialized knot of capillaries to form the glomerulus; the open ends merge to empty into the ureter and thence the bladder. The first step in urine formation is the expression of a protein and cell-free filtrate of blood. As this glomerular filtrate flows down the nephron it is modified by the selective reabsorption of most of the solutes and water and the selective secretion of other solutes to form the final urine. By varying the composition of the final urine, the composition of the interstitial fluid bathing the cells of the body is maintained within the narrow limits compatible with life. From experiments on isolated perfused tubules, a great deal is known about the transport properties of the individual renal tubules, and from whole animal experiments a great deal is known about overall function of the kidney. Lacking is a coherent theory that links microscopic function with overall function. The general method we have devised for modeling this intricate system is to solve the differential equations describing volume and solute flow in the individual tubules against assumed values of solute concentrations and hydrostatic pressure in the vascular interstitial space. Transmural solute and water fluxes computed for the tubes are then substituted into the differential equations for the space. If these are satisfied to some specified tolerance, we have a solution. If not, a correction to the assumed concentrations is computed by a Newton type method. The scheme is iterated until a satisfactory solution is obtained. Our current research is evolving toward more realistic models along two parallel paths: l) Incorporation of more details of the renal anatomy. Here we are moving from models in which the interstitial space is assumed to be radially well mixed toward models in which both the radial and axial distribution of structures are considered. 2) Incorporation of more details of transtubular transport. Our current kidney models describe fluxes of solute and water from tubular lumen to surrounding interstitial space by treating the tubular wall as a single membrane and describing fluxes through it by the phenomenology of irreversible thermodynamics. In models of individual segments this description has been replaced by one that considers the details of transport through cells and intracellular space. These detailed tubular models are being introduced into the whole kidney models.

这项工作的总体目标是综合实验数据 在膜和分子水平上转化为预测数学 哺乳动物肾脏模型有助于理解两者 它的正常和患病功能。 哺乳动物的肾脏由 大量单位（肾单位）并行运行。 每个 肾单位是一根长约 1 厘米、直径约 10 的 -3 次方厘米的管子 直径。 封闭端缠绕在一个特殊的结上 毛细血管形成肾小球；开放端合并成空 输尿管，然后是膀胱。 尿液形成的第一步 是蛋白质和血液无细胞滤液的表达。 作为 这种肾小球滤液沿着肾单位流动，它被 大多数溶质和水的选择性重吸收 选择性分泌其他溶质形成最终尿液。 经过 改变最终尿液的成分， 沐浴身体细胞的间质液维持在 与生活相适应的狭窄界限。 来自孤立的实验 灌注小管，关于运输特性有很多了解 单个肾小管的数据，以及整个动物实验的数据 人们对肾脏的整体功能了解很多。 缺少的是 将微观功能与整体联系起来的连贯理论 功能。 我们设计的用于建模的通用方法 复杂系统是为了求解描述的微分方程 各个管中的体积和溶质流量与假设的 溶质浓度和静水压力值 血管间隙。 透壁溶质和水通量 然后将管的计算结果代入微分中 空间方程。 如果这些满足某些指定 宽容，我们有办法。 如果不是，则对假设进行修正 浓度通过牛顿型方法计算。 该方案是 迭代直至得到满意的解。 我们目前的 研究正在沿着两个平行的方向朝着更现实的模型发展 路径：l) 纳入肾脏解剖结构的更多细节。 这里 我们正在从假设间隙空间的模型转向 径向良好混合的模型，其中径向和 考虑结构的轴向分布。 2) 合并 经管运输的更多细节。 我们目前的肾脏模型 描述溶质和水从管腔到周围环境的通量 通过将管状壁视为单个膜来处理间隙空间 并用不可逆现象学来描述通过它的通量 热力学。 在各个部分的模型中，此描述具有 已被考虑运输细节的替代 细胞和细胞内空间。 这些详细的管状模型是 被引入全肾模型。