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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.

项目概要项目的总体目标是对肾脏液体和电解质转运进行数学建模。健康和疾病。在上一期之前，这个项目已经制作了所有肾脏的模型库肾小管片段，上一时期的首要任务是将这些片段模型连接成一个肾单位。上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，其中髓质成分是计算出来的，而不是指定的。模拟主要代谢紊乱（例如高血糖、高钾血症、碱中毒）、利尿剂使用和遗传运输缺陷需要这个范围的模型。同时，肾脏模型捕捉到总体溶质排泄、间质浓度分布和肾小管内静水压需要额外的工作。具体而言，髓质 Na+、尿素和 NH4+ 浓度低于预期的;远端血流的变化扭曲了整个肾单位的压力。在接下来的一段时间内，目标 1 保留当前模型结构，并解决 Na+、尿素和压力问题。预计调整近髓肾单位运输参数将改善间质组成，并且修改管材顺应性将减轻压力影响。目标 2 解决肾脏 NH4+ 浓度以及 NH4+ 流在肾静脉和尿液之间的分配。这不能通过参数来完成调整，但需要皮质微血管。预计内逆流交换皮质血管可增强氨排泄，同时限制肾静脉氨（如所见酸中毒和肝病）。目标 3 将引入钙作为新模型溶质。肾钙浓度是钠转运的调节剂，具有转化重要性（例如高钙尿症疾病、结石形成）。目标 4 包括实验合作中的模型应用。工作 Tong Wang 博士继续研究流量依赖性钠重吸收在肾脏中的作用囊性疾病。多囊肾病基因可能介导这种血流反应，我们怀疑流量与流量不匹配会导致肾小管压力升高，加剧囊肿形成。对此，目标 1 中对肾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，将节段模型和肾单位模型应用于 Na+ 狂热中的 K+ 排泄州。这些实验通常记录特定转运蛋白密度的变化，以及模型提供一种捕获这些缺陷并估计对其他部分的影响的方法。

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？