Dent's disease, is a disorder that is characterized by low molecular weight proteinuria, aminoaciduria,? glycosuria, polyuria, hyperphosphaturia (Fanconi syndrome) as well as hypercalciuria, nephrocalcinosis,? nephrolithiasis. Dent's disease has been established to be caused by mutations of the CICN-5 gene, the? product of which is CIC-5 a voltage-gated chloride channel expressed in highest abundance in renal tubules? of the proximal nephron. Our preliminary studies in a CICN-5 knockout mouse model, shows that it? recapitulates the features of Dent's disease including hypercalciuria, aminoaciduria, glycosuria, low? molecular weight proteinuria, renal calcifications, and renal failure. THE PRPOSED STUDY WILL HELP? DEFINE THE UNDERLYING MOLECULAR BASIS OF THESE REABSORPTION DEFECTS.? Specific aim 1: How do other CIC channels or CIC-5 exchange regulate apical endocytosis in proximal? tubule cells? 1 A. Do CIC-3 and/or CIC-4 contribute to the residual acidification and apical endocytosis in the? ko cells? 18. Does the over-expression of CIC-3 and CIC-4 restore albumin uptake in CIC-5 ko cells? Does? the chloride/proton exchanger activity of CIC-5 in ko cells restore normal albumin uptake? Specific Aim 2:? What is the relationship between loss of CIC-5 and the downregulation of megalin in the ko proximal tubule? cells? 2A. Is the half-life of megalin shorter in ko versus wt cells? 2B. How is the recycling behavior of? megalin altered in ko versus wt cells? 2C. Does endosomal pH, or lack of CIC-5, regulate megalin? dynamics? Specific Aim 3. How does the loss of CIC-5 lead to changes in the distribution/activity of NHE3? and other apical transporters? 3A. Is NHE3 activity decreased in the proximal tubule, ileum or jejunum of ko? mice? 3B. What are the steady state levels and dynamics of NHE3 in ko proximal tubules cells? 3C. What? are the steady state levels and dynamics of NaPi-lla in ko proximal tubule cells? 3D, Does endosomal pH, or? lack of CIC-5, regulate NHE3 or NaPi-lla dynamics?? The long term goal of this research is to understand how molecular events cause the phenotypical? outcomes of Dent's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK072084-02
Application #
7487971
Study Section
Special Emphasis Panel (ZDK1)
Project Start
2007-09-01
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$291,575
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Singh, Varsha; Yang, Jianbo; Yin, Jianyi et al. (2018) Cholera toxin inhibits SNX27-retromer-mediated delivery of cargo proteins to the plasma membrane. J Cell Sci 131:
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Sarker, Rafiquel; Cha, Boyoung; Kovbasnjuk, Olga et al. (2017) Phosphorylation of NHE3-S719 regulates NHE3 activity through the formation of multiple signaling complexes. Mol Biol Cell 28:1754-1767
Qiang, Xiaoling; Liotta, Anthony S; Shiloach, Joseph et al. (2017) New melanocortin-like peptide of E. coli can suppress inflammation via the mammalian melanocortin-1 receptor (MC1R): possible endocrine-like function for microbes of the gut. NPJ Biofilms Microbiomes 3:31
Cha, Boyoung; Yang, Jianbo; Singh, Varsha et al. (2017) PDZ domain-dependent regulation of NHE3 protein by both internal Class II and C-terminal Class I PDZ-binding motifs. J Biol Chem 292:8279-8290
Yu, Huimin; Hasan, Nesrin M; In, Julie G et al. (2017) The Contributions of Human Mini-Intestines to the Study of Intestinal Physiology and Pathophysiology. Annu Rev Physiol 79:291-312
Foulke-Abel, Jennifer; In, Julie; Yin, Jianyi et al. (2016) Human Enteroids as a Model of Upper Small Intestinal Ion Transport Physiology and Pathophysiology. Gastroenterology 150:638-649.e8
Gupta, Arnab; Schell, Michael J; Bhattacharjee, Ashima et al. (2016) Myosin Vb mediates Cu+ export in polarized hepatocytes. J Cell Sci 129:1179-89
Zachos, Nicholas C; Kovbasnjuk, Olga; Foulke-Abel, Jennifer et al. (2016) Human Enteroids/Colonoids and Intestinal Organoids Functionally Recapitulate Normal Intestinal Physiology and Pathophysiology. J Biol Chem 291:3759-66
Cebotaru, Liudmila; Liu, Qiangni; Yanda, Murali K et al. (2016) Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease. Kidney Int 90:90-9

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