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: 8370374
• 负责人: ALAN M WEINSTEIN
• 金额: $ 18万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-08-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370374
• 关键词: Acetazolamide; Acidosis; Acids; Adverse effects; Affect; Blood; Blood capillaries; Brush Border; Buffers; Cell Volumes; Cell membrane; Cell model; Cells; Collaborations; Computer Simulation; Defect; Disease; Distal; Distal convoluted renal tubule structure; Diuresis; Diuretics; Drug Formulations; Duct (organ) structure; Edema; Electrolyte Disorder; Electrolytes; Epithelium; Equation; Equilibrium; Erythrocytes; Feedback; Functional disorder; Generations; Hemoglobin; Hereditary Disease; Homeostasis; Hypertension; Intervention; Investments; Kidney; Libraries; Limb structure; Linear Models; Liquid substance; Measures; Membrane Transport Proteins; Metabolic; Metabolism; Modeling; Modification; Molecular; Nephrons; Organ; Phenotype; Physiological; Population; Process; Publishing; Renal function; Renal tubule structure; Second Messenger Systems; Signal Transduction; Simulate; Sodium; Solutions; Specific qualifier value; System; Time; Transport Process; Urine; Variant; Water; Work; absorption; base; capillary; cellular microvillus; density; glomerular filtration; hyperkalemia; interstitial; kidney medulla; mathematical model; potassium bicarbonate; response; second messenger; simulation; solute; theories; tool

DESCRIPTION (provided by applicant): The overall objective of this project is mathematical modeling and computer simulation of fluid and electrolyte disorders in kidney tubules. To date, this project has formulated models of glomerulus, proximal convoluted tubule, and all segments from ascending Henle limb, through distal tubule, and collecting duct. In the next investigational period, the first task is to complete the library of renal segmental models, and fashion short- and long-looped nephrons, solved against interstitial composition. These models will simulate axial interaction among segments, as in osmotic diuresis or acetazolamide action, and predict the impact of medullary K+ concentration on distal solute delivery. Solved iteratively, this model will allow representation of the stabilization of distal solute delivery via tubuloglomerular feedback. The second aim will require the major investment of effort for the project period, and this will be to advance the nephron models from a specified interstitium to solving for interstitial concentrations as unknown variables. This aspect of the project is critical to estimating the impact of changing flows and changing transport on peritubular conditions. It extends the classical computational approach to the urine concentrating mechanism, to K+ and acid-base metabolism. Major metabolic derangements, such as hyperkalemia and acidosis, alter renal medullary solutes and thus influence urine composition; this will be the first effort to simulate that impact. The third aim will be to examine cellular homeostasis as a systems approach to cell membrane transporters. The approach will use mathematical control theory to identify transporter ensembles, which can function in a coordinated way to allow large re-absorptive fluxes, while preserving cell volume and composition. These transporter ensembles maybe viewed as "hypothesis generation" with respect to experimental examination of kidney tubules. Finally, experimental collaborations are in progress to examine predictions from this project. Work continues with Dr. Tong Wang to examine flow-dependent proximal tubule transport, specifically our proposal that brush border microvilli are flow mechanosensors. Anew project is planned with Dr. Wang to examine flow-dependent transport in distal nephron, specifically in relation to flow-dependent HCO-3 re-absorption as a consequence of diuretic ad- ministration. Genetic disorders of electrolyte metabolism or pharmacologic intervention general- ly affect a single transporter in a single kidney tubule. However, the impact on overall kidney function maybe far-reaching, affecting other segments, both adjacent and at a distance. Such models can rationalize whole-organ malfunction as the consequence of a molecular defect. PUBLIC HEALTH RELEVANCE: The overall objective of this project is mathematical and computer modeling of fluid and electrolyte disorders in kidney tubules. Hypertension and edema maybe due in part to excessive sodium absorption in one or more regions of the kidney, and treatment of sodium retention with diuretics can have adverse effects on blood levels of potassium and bicarbonate. This modeling effort will provide a tool for simulation of both the disorders and their treatment.

项目描述（由申请人提供）：本项目的总体目标是对肾小管中的液体和电解质紊乱进行数学建模和计算机模拟。到目前为止，本项目已经建立了肾小球、近曲小管和从上行Henle肢到远端小管和集管的所有节段的模型。在接下来的研究阶段，首要任务是完成肾节段模型库，并时尚短和