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, theproduct of which is CIC-5 a voltage-gated chloride channel expressed in highest abundance in renal tubulesof the proximal nephron. Our preliminary studies in a CICN-5 knockout mouse model, shows that itrecapitulates the features of Dent's disease including hypercalciuria, aminoaciduria, glycosuria, lowmolecular weight proteinuria, renal calcifications, and renal failure. THE PRPOSED STUDY WILL HELPDEFINE THE UNDERLYING MOLECULAR BASIS OF THESE REABSORPTION DEFECTS.
Specific aim 1 : How do other CIC channels or CIC-5 exchange regulate apical endocytosis in proximaltubule cells? 1 A. Do CIC-3 and/or CIC-4 contribute to the residual acidification and apical endocytosis in theko cells? 18. Does the over-expression of CIC-3 and CIC-4 restore albumin uptake in CIC-5 ko cells? Doesthe 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 tubulecells? 2A. Is the half-life of megalin shorter in ko versus wt cells? 2B. How is the recycling behavior ofmegalin altered in ko versus wt cells? 2C. Does endosomal pH, or lack of CIC-5, regulate megalindynamics? Specific Aim 3. How does the loss of CIC-5 lead to changes in the distribution/activity of NHE3and other apical transporters? 3A. Is NHE3 activity decreased in the proximal tubule, ileum or jejunum of komice? 3B. What are the steady state levels and dynamics of NHE3 in ko proximal tubules cells? 3C. Whatare the steady state levels and dynamics of NaPi-lla in ko proximal tubule cells? 3D, Does endosomal pH, orlack of CIC-5, regulate NHE3 or NaPi-lla dynamics?The long term goal of this research is to understand how molecular events cause the phenotypicaloutcomes of Dent's disease.
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