Optimal Mathematical Models of Renal Transport Processes

描述（由申请人提供）：优化方法为研究数学模型中的参数和解决方案之间的关系提供了系统的手段。在肾脏系统中，模型涉及大量参数，并且当测量存在时，它们与一些不确定性相关联。此外，实验数据通常是间接的，因为测量的变量很少是实际参数，但通常是依赖于参数的函数变量，并且是可测量的。一旦制定了肾过程的模型，就可以使用优化方法通过搜索导致与测量的响应一致的模型行为的合理模型参数的集合来验证模型。此外，优化分析可以揭示参数之间的协同作用，产生最佳的功能行为，如最大的能源效率。然而，应用优化方法来解决复杂的生物模型往往是困难的，因为大量的参数，因为问题可能是不适定的。 在这个应用程序中，我们的目标是开发策略和方法，在肾脏生理学中使用的优化方法，并使用这些方法来研究两个基本问题。第一个是关于肾逆流系统的尿浓缩能力的决定因素。第二部分着重于肾上皮细胞中不同共转运蛋白的功能和结合序列构型。 这些研究将为了解肾脏逆流系统，以及上皮细胞协同转运蛋白的最佳功能和结构提供新的见解。它们还将为应用优化方法研究肾功能的最佳方法提供新的见解。由于所得到的最佳模型的协同转运蛋白将通过万维网作为一个工具箱的一部分，这些研究将提供肾上皮生理学家与模拟工具的实验设计和数据分析。 如果成功，这些研究将提供一种从现有数据中提取有关肾系统功能的额外信息的方法。由于肾脏逆流系统和上皮细胞中的协同转运蛋白都参与了肾脏水盐排泄的调节，这些研究最终可能有助于了解肾脏在高血压和与尿浓缩缺陷相关的疾病中的作用。

DESCRIPTION (provided by applicant): Optimization methods provide systematic means for studying the relationship between the parameters and the solutions in mathematical models. In renal systems the models involve a large number of parameters and, when measurements exist, they are associated with some uncertainty. Further, the experimental data is often indirect, in that the measured variable is seldom the actual parameter, but is normally a functional variable that is dependent upon the parameters and is measurable. Once a model of a renal process is formulated, optimization methods can be used to validate the model by searching for sets of reasonable model parameters that result in model behavior consistent with measured responses. Further, optimization analysis can reveal synergism between parameters that yield optimal functional behaviors, such as maximal energy efficiency. However, application of optimization methods to complex biological models is often difficult because of the large numbers of parameters, and because the problem may be ill-posed. In this application we aim to develop strategies and approaches for the use of optimization methods in renal physiology, and to use these methods to investigate two fundamental problems. The first concerns the determinants of urine concentrating ability of the renal countercurrent system. The second focuses on the function and binding sequence configuration of different co transporters in renal epithelial cells. These studies will provide new insights into the renal countercurrent system, and optimal function and structure of co transporters in epithelial cells. They will also provide new insight into the best approaches for application of optimization methods to study renal function. Because the resultant optimal models of the co transporters will be made available as part of a toolbox through the world wide web, these studies will provide renal epithelial physiologists with simulation tools for experimental design and data analysis. If successful, the studies will provide a means to extract addition information about renal system function from existing data. Because the renal countercurrent system and the co transporters in epithelial cells are both involved in the regulation of renal water and salt excretion, these studies may eventually facilitate progress in understanding the renal role in hypertension and in diseases associated with defects in urine concentration.