ADVANCE Fellows Award: Mathematical Modeling of Renal Physiology

ADVANCE 研究员奖：肾脏生理学数学建模

• 批准号: 0340654
• 负责人: Anita Layton
• 金额: --
• 依托单位: Duke University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0340654&HistoricalAwards=false
• 关键词: ADVANCE; Fellows; Award; Mathematical; Modeling

The urine concentrating mechanism (UCM), which gives mammals the capability to produce hypertonic urine, is localized in the renal medulla. In the outer medulla, the UCM is driven by active NaCl transport from thick ascending limbs, coupled with a countercurrent flow configuration of nephrons and vessels; in the inner medulla, the underlyingprinciples of the UCM remain to be determined. To better understand the mammalian UCM, the PI seeks to develop a dynamic formulation of a highly-detailed region-based mathematical model of the renal cortex and medulla of the rat kidney. The ``region-based'' modeling approach represents radial organization of nephrons and vessels, as revealed in anatomic studies, and captures the preferential interactions among medullary structures. The model will incorporate and evaluate experimental findings not previously included in models, including the implications of recent immunolabeling experiments. To investigate the interactions between UCM and tubuloglomerular feedback (TGF) mechanism, the PI will develop a dynamic epithelial transport model of the proximal tubule, and incorporate that model into a TGF framework.The resulting model may provide integrated insight into pathogenesis of diseases in which dietary salt intake has a paradoxical effect on glomerular filtration rate, and in which extracellular fluid volume or the regulation of sodium transport are deranged.In addition, using the above models, the PI will generate animations of distributions of filtered solutes and develop user-friendly modeling packages for use by experimentalists.The overall objective of this project is to use analysis and computational mathematics to gain a better understanding of a long-standing mystery in traditional physiology: the mechanism by which mammals produce concentrated urine.Indeed, although the passive mechanism is frequently given in physiologytextbooks as an explanation for the production of a concentrated urinein mammals, it does not produce a satisfactory concentration gradient in computer simulations. Through the development of a series of mathematical models, the PI seeksto assess the validity of certain modeling assumptions. Moreover, the models may provide insights into questions such as: What are the impacts of unexpected experimental findings that challenge accepted notions of the concentrating mechanism?What is the role of the tubuloglomerular feedback system (which regulates the rateof fluid entry into the nephrons, which are functional units of the kidney)in the regulation of sodium excretion in both healthy and hypertensive rats?In particular, why does renal blood flow vary inversely with dietary salt in both diabetic patients and rats with experimental diabetes, when the opposite effect is expected?Another objective of this project is to disseminate modeling methodologies and results, in part through the applications of computer visualization techniques.The proposed modeling packages to be developed should encourage experimentalists to use modeling techniques to gain a better understanding of the significance of much new experimental data now emerging through techniques involving computer-assisted micro-anatomy and transgenic animals.

哺乳动物产生高渗尿液的尿液浓缩机制（UCM）位于肾髓质。在外髓质，UCM由来自粗升肢的活跃NaCl运输驱动，再加上肾单位和血管的逆流配置；在内髓质中，UCM的基本原理仍有待确定。为了更好地理解哺乳动物的UCM， PI试图开发一个基于区域的大鼠肾脏皮质和髓质的高度详细的数学模型的动态公式。“基于区域”的建模方法代表了肾单位和血管的径向组织，正如解剖学研究所揭示的那样，并捕获了髓质结构之间的优先相互作用。该模型将纳入和评估以前未包括在模型中的实验结果，包括最近免疫标记实验的影响。为了研究UCM与小管肾小球反馈（TGF）机制之间的相互作用，PI将建立近端小管的动态上皮运输模型，并将该模型纳入TGF框架。由此产生的模型可能为以下疾病的发病机制提供综合见解：饮食盐摄入对肾小球滤过率有矛盾的影响，细胞外液容量或钠转运调节紊乱。此外，使用上述模型，PI将生成过滤溶质分布的动画，并开发用户友好的建模包供实验人员使用。该项目的总体目标是利用分析和计算数学来更好地理解传统生理学中一个长期存在的谜团：哺乳动物产生浓缩尿液的机制。事实上，尽管生理教科书中经常给出被动机制作为哺乳动物产生浓尿的解释，但在计算机模拟中，它并不能产生令人满意的浓度梯度。通过一系列数学模型的发展，PI试图评估某些建模假设的有效性。此外，这些模型可能为以下问题提供见解：挑战公认的集中机制概念的意外实验发现的影响是什么？小管肾小球反馈系统（调节液体进入肾单位的速率，肾单位是肾脏的功能单位）在调节健康和高血压大鼠钠排泄中的作用是什么？特别是，为什么糖尿病患者和实验性糖尿病大鼠的肾血流量与饮食盐成反比，而预期相反的效果呢？这个项目的另一个目标是传播建模方法和结果，部分是通过计算机可视化技术的应用。拟开发的建模包应鼓励实验人员使用建模技术，以便更好地理解现在通过涉及计算机辅助显微解剖和转基因动物的技术出现的许多新实验数据的意义。