Mathematical models are formulated that represent an epithelium as a system of compartments and bounding membranes and permit the computer simulation of normal and pathological states. This project also undertakes the analysis of simplified, approximate models, which may be used in the interpretation of experimental data. The primary aim of this project remains the development of a mathematical model of proximal tubule, and effort will be focused on acid-base transport. A segmented tubule model will be developed, and the impact of the pH dependence of the Na+/H+ exchanger will be examined in simulations of acid-base disturbances. A second question to be addressed is the role of the luminal Na+/H+ exchanger in mediating glomerulotubular balance. Experimental collaborations are planned which will test previous model predictions regarding the importance of paracellular convective fluxes.
A second aim of this project is to develop the theory of isotonic volume regulation during fluctuations of net transport. In the proposed work, an analytical model will be extended to estimate isotonic volume regulation and conditions for dynamical stability will be sought. In electrolyte simulations of principal cells and proximal tubule cells, we will examine the hypothesis that cell pH is a key signal for volume regulation. In particular the behavior of pH-dependent K+ channels, pH- dependent Na+/H+ exchange, and pH-dependent Na+-K+ ATPase will be considered, and the question posed is whether such mechanisms are adequate for the variety of volume challenges. The third effort will be to extend and test the current CCT model. The extension will be the full collecting duct, and will be used to simulate currently available clinical tests of """"""""distal nephron"""""""" acidification. The goal of this effort is to see whether these tests can indeed be used to infer such defects as H+-pump failure, enhanced backleak, or voltage defects. This will be the first model of this structure and the first tool to be able to give an estimate of the sensitivity of these tests. Some of the predictions of the CCT model will also be tested in experimental collaborations. In particular the hypothesis to be examined is that alkalosis decreases paracellular Cl- permeability, and thus promotes K+ secretion.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Physiology Study Section (PHY)
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Wang, Tong; Weinbaum, Sheldon; Weinstein, Alan M (2017) Regulation of glomerulotubular balance: flow-activated proximal tubule function. Pflugers Arch 469:643-654
Weinstein, Alan M (2017) A mathematical model of the rat kidney: K+-induced natriuresis. Am J Physiol Renal Physiol 312:F925-F950
Weinstein, Alan M (2016) Systems biology of the cortical collecting duct. J Physiol 594:5733-5734
Perez Bay, Andres E; Schreiner, Ryan; Benedicto, Ignacio et al. (2016) The fast-recycling receptor Megalin defines the apical recycling pathway of epithelial cells. Nat Commun 7:11550
Weinstein, Alan M (2015) A mathematical model of the rat nephron: glucose transport. Am J Physiol Renal Physiol 308:F1098-118
Nanami, Masayoshi; Lazo-Fernandez, Yoskaly; Pech, Vladimir et al. (2015) ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. I. Stilbene-sensitive Cl- secretion. Am J Physiol Renal Physiol 309:F251-8
Terker, Andrew S; Zhang, Chong; McCormick, James A et al. (2015) Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride. Cell Metab 21:39-50
Nanami, Masayoshi; Pech, Vladimir; Lazo-Fernandez, Yoskaly et al. (2015) ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. II. Bafilomycin-sensitive H+ secretion. Am J Physiol Renal Physiol 309:F259-68
Du, Zhaopeng; Weinbaum, Sheldon; Weinstein, Alan M et al. (2015) Regulation of glomerulotubular balance. III. Implication of cytosolic calcium in flow-dependent proximal tubule transport. Am J Physiol Renal Physiol 308:F839-47
Weinstein, Alan M (2015) A mathematical model of rat proximal tubule and loop of Henle. Am J Physiol Renal Physiol 308:F1076-97

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