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Theory of Solute and Water Transport Across Epithelia

跨上皮细胞的溶质和水运输理论

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要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。在上一阶段之前，该项目已经产生了一个所有肾脏的模型库，小管节段，最后一节课的第一个任务是将这些节段模型连接成一个肾单位最后一个阶段的主要努力是增加延髓微循环，将肾单位转换为肾脏模型，其中计算髓质组成，而不是指定。模拟主要代谢紊乱（例如高血糖症、高钾血症、糖尿病），利尿剂使用和遗传运输缺陷需要这种范围的模型。同时，肾脏模型捕捉到总体溶质排泄、间质浓度分布和小管内流体静压需要额外的工作。具体来说，髓质Na+、尿素和NH 4+浓度低于远端血流的变化使沿着整个肾单位的压力发生扭曲。下一节课，目标1保留当前模型结构，并解决Na+和尿素以及压力问题。预计在调节髓质肾单位转运参数将改善间质组成，修正管顺应性将减轻压力效应。目标2解决肾脏NH 4+浓度以及NH 4+在肾静脉和尿液之间流动的分配。这不能用参数来完成调整，但需要皮质微血管。预计内部逆流交换皮质血管可增强氨排泄，同时限制肾静脉氨（如图所示酸中毒和肝病）。目的3是引入钙作为新的模型溶质。肾钙浓度是钠转运的调节剂，并且具有翻译重要性（例如高钙尿疾病、结石形成）。目标4包括在实验合作中的模型应用。工作继续与王彤博士，研究流量依赖性钠重吸收的作用，在肾脏囊性疾病多囊肾病基因可能介导这种血流反应，我们怀疑，不能使流量与流量相匹配会升高小管压力，加剧囊肿形成。在这方面，委员会认为，在目标1中对小管压力和顺应性的关注将是该目标的基础。协作是继续与Larry Palmer博士将节段和肾单位模型应用于Na+-avid states.这些实验通常记录了特定转运蛋白密度的变化，提供一种捕获这些缺陷并估计对其他部分影响的方法。

项目成果

期刊论文数量（64）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
Zhu,Quansheng;Shao,XuesiM;Kao,Liyo;Azimov,Rustam;Weinstein,AlanM;Newman,Debra;Liu,Weixin;Kurtz,Ira
通讯作者：
Kurtz,Ira

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？