THEORY OF SOLUTE AND WATER TRANSPORT ACROSS EPITHELIA

数学模型被表述为将上皮表示为 隔间和包围膜的系统，并允许计算机 模拟正常和病理状态。这个项目还 承担简化的近似模型的分析，这些模型可能是 用于解释实验数据。这样做的主要目的是 该项目仍在开发一个近端的数学模型 小管，努力将重点放在酸碱运输上。一个分段的 将建立肾小管模型，并研究其对pH依赖性的影响 Na+/H+交换器将在酸碱模拟中进行检验 骚乱。第二个需要解决的问题是 管腔Na+/H+交换器在调节肾小球肾小管平衡中的作用 计划进行试验性协作，以测试先前的模型 关于胞外对流通量重要性的预测。 这个项目的第二个目标是发展等张体积理论。 净运输量波动期间的监管。在拟议的工作中， 分析模型将被扩展以估计等渗体积量。 将寻求动态稳定的规则和条件。在……里面 主细胞和近曲小管细胞的电解液模拟 将检验细胞pH是体积的关键信号这一假设 监管。尤其是依赖于pH的K+通道的行为，pH- 依赖于Na+/H+交换和依赖于pH的Na+-K+ATPase 考虑过了，提出的问题是这种机制是否 足以应对各种数量挑战。第三项努力将是 扩展和测试当前的CCT模型。分机部分将是完整的 收集风管，并将用于模拟当前可用的 远端肾单位酸化的临床试验。这样做的目的是 努力看看这些测试是否真的可以用来推断 H+泵故障、反泄漏增强或电压缺陷等缺陷。这 将是这个结构的第一个模型，也是第一个能够 对这些测试的敏感性进行估计。其中一些 CCT模型的预测也将在实验中得到验证 合作。特别是，要检验的假设是 碱中毒降低细胞旁氯离子的通透性，从而促进K+ 分泌物。

Mathematical models are formulated that represent an epithelium as a system of compartments and bounding membranes and permit the computer simulation of normal and pathological states. This project also undertakes the analysis of simplified, approximate models, which may be used in the interpretation of experimental data. The primary aim of this project remains the development of a mathematical model of proximal tubule, and effort will be focused on acid-base transport. A segmented tubule model will be developed, and the impact of the pH dependence of the Na+/H+ exchanger will be examined in simulations of acid-base disturbances. A second question to be addressed is the role of the luminal Na+/H+ exchanger in mediating glomerulotubular balance. Experimental collaborations are planned which will test previous model predictions regarding the importance of paracellular convective fluxes. A second aim of this project is to develop the theory of isotonic volume regulation during fluctuations of net transport. In the proposed work, an analytical model will be extended to estimate isotonic volume regulation and conditions for dynamical stability will be sought. In electrolyte simulations of principal cells and proximal tubule cells, we will examine the hypothesis that cell pH is a key signal for volume regulation. In particular the behavior of pH-dependent K+ channels, pH- dependent Na+/H+ exchange, and pH-dependent Na+-K+ ATPase will be considered, and the question posed is whether such mechanisms are adequate for the variety of volume challenges. The third effort will be to extend and test the current CCT model. The extension will be the full collecting duct, and will be used to simulate currently available clinical tests of "distal nephron" acidification. The goal of this effort is to see whether these tests can indeed be used to infer such defects as H+-pump failure, enhanced backleak, or voltage defects. This will be the first model of this structure and the first tool to be able to give an estimate of the sensitivity of these tests. Some of the predictions of the CCT model will also be tested in experimental collaborations. In particular the hypothesis to be examined is that alkalosis decreases paracellular Cl- permeability, and thus promotes K+ secretion.