Theory of Solute and Water Transport Across Epithelia

跨上皮细胞的溶质和水运输理论

• 批准号: 10425337
• 负责人: ALAN M WEINSTEIN
• 金额: $ 21.19万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425337
• 关键词: Acidosis; Address; Adverse effects; Alkalosis; Ammonia; Attention; Blood; Blood Vessels; Blood flow; Calcium; Caliber; Carbon Dioxide; Collaborations; Computers; Cyst; Cystic Kidney Diseases; Data; Defect; Disease; Distal; Diuretics; Dopamine Antagonists; Duct (organ) structure; Edema; Electrolyte Disorder; Electrolytes; Epithelial; Excretory function; Failure; Feedback; Foundations; Genes; Genetic; Health; Hydrostatic Pressure; Hyperglycemia; Hypertension; Juxtamedullary Nephron; Kidney; Libraries; Limb structure; Liquid substance; Liver diseases; Mathematics; Measures; Mediating; Metabolic; Metabolism; Microcirculation; Modeling; Mus; Nephrons; Performance; Perfusion; Physiology; Play; Polycystic Kidney Diseases; Production; Proprotein Convertase 2; Rattus; Renal tubule structure; Role; Series; Signal Transduction; Sodium; Source; Specific qualifier value; Structure; Structure of renal vein; Treatment Side Effects; Tubular formation; Urea; Urine; Variant; Venous; Water; Work; absorption; antidiuretic; density; experimental study; hypercalciuria; hyperkalemia; improved; in vivo; interstitial; mathematical model; potassium bicarbonate; predictive modeling; preservation; pressure; renal calcium; response; simulation; solute; theories; tool

PROJECT SUMMARY The overall project objective has been mathematical modeling of renal fluid and electrolyte transport in health and disease. Prior to the last period, this project had produced a model library of all kidney tubule segments, and the first task of the last period was to concatenate these segmental models into a nephron. The major effort of the last period was adding the medullary microcirculation, to advance the nephron to a kidney model, in which medullary composition was calculated, rather than specified. Simulation of major metabolic derangements (e.g. hyperglycemia, hyperkalemia, alkalosis), diuretic use, and genetic transport defects require a model of this scope. While, the kidney model captured overall solute excretion, interstitial concentration profiles and intratubular hydrostatic pressures need additional work. Specifically, medullary Na+ and urea and NH4+ concentrations were lower than expected; and changes in distal flow distorted pressures along the entire nephron. In the next period, Aim 1 preserves current model structure, and addresses Na+ and urea and pressure. It is expected that adjusting juxtamedullary nephron transport parameters will improve interstitial composition, and that revising tubular compliance will mitigate pressure effects. Aim 2 addresses renal NH4+ concentrations and partitioning of NH4+ flow between renal vein and urine. This cannot be done with parameter adjustments, but requires cortical microvasculature. It is expected that countercurrent exchange within cortical blood vessels can enhance ammonia excretion, while limiting renal venous ammonia (as seen in acidosis and liver disease). Aim 3 will be introduce calcium as a new model solute. Renal calcium concentration is a regulator of sodium transport, and of translational importance (e.g. hypercalciuric disorders, stone formation). Aim 4 comprises model application in experimental collaborations. Work continues with Dr. Tong Wang, examining the role of flow-dependent sodium reabsorption in renal cystic disease. A polycystic kidney disease gene may mediate this flow-response, and we suspect that failure to match fluxes to flows elevates tubule pressures, exacerbating cyst formation. In this regard, attention in Aim 1 to tubule pressures and compliance will be foundational for this aim. Collaboration is continuing with Dr. Larry Palmer to apply segmental and nephron models to K+ excretion in Na+-avid states. These experiments typically document changes in specific transporter densities, and the models provide a means of capturing these defects and estimating impact on other segments.

项目总结 整个项目的目标是建立肾脏液体和电解质转运的数学模型。 健康和疾病。在上一个阶段之前，这个项目已经产生了一个全肾的模型库 小管分段，最后一个阶段的第一个任务是将这些分段模型连接成一个 尼龙。最后一期的主要工作是增加髓质微循环，以促进 肾单位到肾脏模型，在该模型中，髓成分是计算的，而不是指定的。 模拟主要代谢紊乱(如高血糖、高钾、碱中毒)、利尿剂 使用，而遗传运输缺陷需要一个这种范围的模型。同时，肾脏模型捕捉到了 总溶质排泄量、间质浓度分布和肾小管内静水压力需要 额外的工作。具体地说，髓内Na+、尿素和NH4+浓度低于 预期的；远端血流的变化扭曲了沿整个肾单位的压力。在下一阶段， 目标1保留了现有的模型结构，并解决了Na+、尿素和压力问题。预计 调整延髓旁肾单位转运参数将改善间质成分， 修改肾小管顺应性将减轻压力效应。目标2解决肾脏NH4+浓度问题 肾静脉和尿液之间的NH4+流量分配。这不能用参数来完成 调整，但需要皮质微血管。预计内部的逆流交换 皮质血管可以增加氨的排泄，同时限制肾静脉的氨(如图所示 酸中毒和肝病)。目标3将引入钙作为一种新型溶质。肾钙 浓度是钠转运的调节器，并具有翻译重要性(例如高钙尿症 紊乱、结石形成)。目标4包括模型在实验合作中的应用。工作 王彤博士继续研究肾脏中血流依赖的钠重吸收的作用 囊性疾病。一个多囊肾病基因可能介导了这种流动反应，我们怀疑 流量与流量不匹配会导致肾小管压力升高，从而加剧囊性病变的形成。在这方面， 目标1中对小管压力和顺应性的关注将是实现这一目标的基础。协作是 继续与Larry Palmer博士合作，将节段性和肾单位模型应用于Na+-Avid患者的K+排泄 各州。这些实验通常记录特定转运体密度的变化，以及模型 提供一种捕获这些缺陷并估计对其他细分市场的影响的方法。

项目成果

A mathematical model of the inner medullary collecting duct of the rat: pathways for Na and K transport.

• DOI: 10.1152/ajprenal.1998.274.5.f841
• 发表时间: 1998-05
• 期刊: American journal of physiology. Renal physiology
• 作者: A. Weinstein

The diabetic proximal tubule: part of the problem, and part of the solution?

糖尿病近曲小管：问题的一部分，解决方案的一部分？

• DOI: 10.1152/ajprenal.00272.2014
• 发表时间: 2014
• 期刊: American journal of physiology. Renal physiology
• 作者: Weinstein,AlanM

A mathematical model of rat collecting duct. II. Effect of buffer delivery on urinary acidification.

大鼠集合管的数学模型。

• DOI: 10.1152/ajprenal.00163.2002
• 发表时间: 2002
• 期刊: American journal of physiology. Renal physiology
• 作者: Weinstein,AlanM

A mathematical model of rat distal convoluted tubule. II. Potassium secretion along the connecting segment.

大鼠远曲小管的数学模型。

• DOI: 10.1152/ajprenal.00044.2005
• 发表时间: 2005
• 期刊: American journal of physiology. Renal physiology
• 作者: Weinstein,AlanM

Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis.

错义突变 T485S 改变 NBCe1-A 电性，导致近端肾小管酸中毒。

• DOI: 10.1152/ajpcell.00044.2013
• 发表时间: 2013
• 期刊: American journal of physiology. Cell physiology
• 作者: Zhu,Quansheng;Shao,XuesiM;Kao,Liyo;Azimov,Rustam;Weinstein,AlanM;Newman,Debra;Liu,Weixin;Kurtz,Ira
• 通讯作者: Kurtz,Ira